BRPI0714725A2 - AT LEAST ONE CHEMICAL ENTITY, COMPOSITION, AND METHOD TO TREAT A PATIENT WHO HAS A DISEASE - Google Patents

Abstract

AT LEAST ONE CHEMICAL ENTITY, COMPOSITION, AND METHOD TO TREAT A PATIENT WHO HAS A DISEASE. Certain chemical entities and methods of use are provided for modulating skeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, Skeletal troponin 1, skeletal tiny skeletal troponin, including fragments and isoforms, as well as a skeletal sarcomere, and methods of use. in the treatment of obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, postoperative and post traumatic muscle weakness, neuromuscular disease and other indications.

Description

"AT LEAST ONE CHEMICAL ENTITY, COMPOSITION, AND METHOD TO TREAT A PATIENT WHO HAS A DISEASE"

This application claims the benefit of US Provisional Patent Application No. 60 / 835,272 filed August 2, 2006 and US Provisional Patent Application No. 60 / 921,054 filed March 30, 2007, each of which is incorporated. here by reference for all purposes.

Certain chemical entities that modulate skeletal myosone, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T and skeletal muscle, including fragments and isoforms, as well as skeletal sarcomere are provided. Also provided are certain chemical entities, pharmaceutical compositions and methods of treating one or more obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, postoperative and posttraumatic muscle weakness, and neuromuscular disease.

The cytoskeleton of skeletal and cardiac cells is unique compared to that of other cells. It consists of an almost crystalline formation of closely packed cytoskeletal proteins called a sarcomere. The sarcomere is elegantly organized as an interdigitation formation of thin and thick filaments. The thick filaments are composed of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis in force and directed motion. The thin filaments are composed of actin monomers arranged in a helical formation. There are four regulatory proteins attached to the actin filaments that allow the contraction to be modulated by calcium ions. An intracellular calcium influx initiates muscle contraction; the thick and thin filaments slide together driven by repetitive interactions of the myosin motor domains with the thin actin filaments. Myosin is the most widely studied of all motor proteins. Of the thirteen distinct myosin classes of human cells, the myosin-II class is responsible for contraction of skeletal, cardiac, and smooth muscle. This myosin class is significantly different in amino acid composition and total myosin structure from the other twelve distinct classes. Myosin II consists of two globular head domains linked together by a long spiral-coiled alpha-helical tail that resembles other myosins-II to form the nucleus of the sarcomere's thick filament. Globular heads have a catalytic domain in which actin binds and myosin ATP functions occur. Once bound to an actin filament, phosphate release (cf. ATP to ADP) results in a change in the structural conformation of the catalytic domain, which in turn alters the orientation of the lever arm domain by binding to the light chain. , which extends from the globular head; This movement is called the force course. This change of orientation of the myosin head relative to actin causes its thick filament to be a part for moving with respect to the thin actin filament to which it is attached. The detachment of the globular head from the actin (also Ca + 2 modulated) filament coupled with the return of the catalytic domain and light chain to its starting conformation / orientation completes the contraction and relaxation cycle responsible for intracellular movement and muscle contraction.

Tropomyosin and troponin mediate the effect of calcium on interaction on actin and myosin. The skeletal troponin complex regulates the action of several actin units at the same time and consists of three polypeptide chains: skeletal troponin C, which binds to calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin.

Abnormal contraction of skeletal muscle is thought to be a pathogenetic cause of several disorders, including obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, postoperative and posttraumatic muscle weakness, and neuromuscular disease, which present serious problems. health as adult diseases. Contraction and relaxation of skeletal muscle are mainly controlled by increases and decreases in intracellular calcium.

Therefore, there is a need for the development of new compounds that modulate skeletal muscle. There remains a need for agents to explore new mechanisms of action that may have better results in terms of symptom relief, safety and patient mortality, both in the short term and long term and improved therapeutic index.

At least one chemical entity chosen from the compounds of formula I and compounds of formula II is provided:

-N / n ^ ^ N

OH

:The

Ri N Ri N

R2 R 2

Formula II

and pharmaceutically acceptable salts thereof, wherein R 1 and R 4 are independently selected from hydrogen, halo, hydroxy, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, alkoxy optionally substituted, optionally substituted aminocarbonyl, sulfonyl, sulfanyl, sulfinyl, carboxy, optionally substituted alkoxycarbonyl, and cyano; and alternatively R4 and R1 taken together with any intervening atoms form a fused ring system selected from optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused cycloalkyl, and optionally substituted fused heterocycloalkyl; and

R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;

since

R1 is not hex-1-enyl; and provided that the compound of Formula I or the compound of Formula II is not

(S) -6-bromo-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

1,5,6-trimethyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 1-methyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1- (3-nitrobenzyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

5- (hydroxymethyl) -1,6-dimethyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -

1- (piperidin-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one. Also provided is a pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least one chemical entity described herein.

Methods are also provided for treating a patient having a chosen disease of obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, post-surgical and post-traumatic muscle weakness and neuromuscular disease, comprising administering to the patient a therapeutically effective amount of at least one chemical entity described herein.

Also provided is a method of treating one or more obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, postoperative and posttraumatic muscle weakness, disease.

one;

one;

15

one; or neuromuscular and other indications in a mammal, which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein or a pharmaceutical composition comprising a pharmaceutically acceptable excipient, vehicle or adjuvant and at least one chemical entity described here.

Also provided is a method for treating a patient having a disease responsive to modulation of one or more skeletal myosin, skeletal actin, skeletal tropomycin, skeletal troponin C, skeletal troponin I, and skeletal muscle, including fragments and isoforms thereof, as well as the skeletal sarcomere in a mammal, which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein or a pharmaceutical composition comprising a pharmaceutically acceptable excipient, vehicle or adjuvant and at least one chemical entity described here.

Also provided is a method for treating a patient having a disease responsive to potentiation of one or more skeletal myosin, skeletal actin, skeletal troponin C, skeletal troponin I, skeletal troponin T and skeletal muscle, including fragments and isoforms thereof, as well as the skeletal sarcomere in a mammal, which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein or a pharmaceutical composition comprising a pharmaceutically acceptable excipient, vehicle or adjuvant and at least one chemical entity described here.

Also provided is a method for treating a patient having a disease responsive to inhibition of one or more of skeletal myosin, skeletal actin, skeletal troponin C, skeletal troponin I, skeletal troponin T and skeletal muscle, including fragments and isoforms thereof, as well as the skeletal sarcomere in a mammal, which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein or a pharmaceutical composition comprising a pharmaceutically acceptable excipient, vehicle or adjuvant and at least one chemical entity described here.

Other aspects and embodiments will be apparent from those skilled in the art by the following detailed description.

As used in this report, words and phrases are

generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

The following abbreviations and terms have the meanings indicated from beginning to end:

Ac = acetyl

APCI = atmospheric pressure chemical ionization

atm = atmosphere

Boc = tert-butoxycarbonyl

c- = cycle

CBZ = carbobenzyloxy = benzyloxycarbonyl

ICD = carbonyldiimidazole

DCM = dichloromethane = methylene chloride = CH 2 Cl 2

DIEA = DIPEA = N, N-diisopropylethylamine

DMF = N, N-dimethylformamide

DMSO = dimethyl sulfoxide

(DPPF) PdCl 2 = [1,1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II)

Et = ethyl

EtOAc = ethyl acetate

EtOH = ethanol g

GC

h or hr HPLC i-

kg or kg I or L LCMS m / z Me NMP NMR MPLC min mg

mL or ml MW n-Ph

(PH3P) 4Pd (PH3P) 2PdCl2 rt or RT s-

TES TMS TFA THF TLC

: gram

: gas chromatography: hour

: high pressure liquid chromatography: iso

: kilogram: liter

: mass spectrometry-liquid chromatography: mass to charge ratio: methyl

; 1-methyl-2-pyrrolidinone: nuclear magnetic resonance medium pressure liquid chromatography minute milligram milliliter normal microwave phenyl

teracis (triphenylphosphine) palladium (0)

dichlorobis (triphenylphosphine) palladium (II)

room temperature

sec = secondary

tert- = tertiary

triethylsilyl or triethylsilane

trimethylsilyl or trimethylsilane

trifluoroacetic acid

tetrahydrofuran

UV = ultraviolet thin layer chromatography

vol = equivalent volume in ml / g or l / kg for reagent

limiting unless otherwise indicated

By "optional" or "optionally" we mean that the event or circumstance subsequently described may or may not occur and that the description includes examples where the event or circumstance occurs and examples where it does not. For example, "optionally substituted alkyl" embraces both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impracticable, synthetically unenforceable and / or inherently stable.

"Alkyl" embraces straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example, C1 -C6 alkyl embraces both straight and branched chain alkyl of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is cited, all straight and branched chain versions having that number of carbons are intended to be covered; thus, for example, "butyl" means the inclusion of n-butyl, sec-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to alkyl groups having one to seven carbons. In certain embodiments, "lower alkyl" refers to alkyl groups having one to six carbons. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and similar. Alkylene is a subset of alkyl, with reference to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, C1-4 alkylene indicates a covalent bond and C1-4 alkylene is a methylene group.

"Alkenyl" refers to a straight or branched chain unsaturated alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen molecule from the adjacent carbon atoms of the precursor alkyl. The group may be in useful or trans configuration around the double bond (s). Typical alkenyl groups include but are not limited to ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2 -en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms. "Lower alkenyl" refers to alkenyl groups having two to six carbons.

"Alkynyl" refers to a straight or branched chain unsaturated alkyl group having at least one triple carbon-carbon bond derived from the removal of two hydrogen molecules from the adjacent carbon atoms of the precursor alkyl. Typical alkynyl groups include but are not limited to ethinyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms. "Lower alkynyl" refers to alkynyl groups having two to six carbons.

"Cycloalkyl" denotes a nonaromatic carbocyclic ring, usually having from 3 to 7 carbon atoms in the ring. The ring may be saturated or have one or more carbon-carbon double bonds. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groups such as norbornane.

The term "alkoxy" refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof, attached to the precursor structure by oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. "Lower alkoxy" refers to alkoxy groups containing one to six carbons.

The term "substituted alkoxy" refers to alkoxy in which the alkyl constituent is substituted (i.e. -0- (substituted alkyl)), wherein "substituted alkyl" refers to alkyl in which one or more (such as up to 5, for example up to 3) hydrogen atoms are substituted by a substituent independently chosen from:

-Ra, -ORb, optionally substituted amino (including - NRcCORb, -NRcCO2R3, -NRcCONRbRc, -NRbC (NRc) NRbRc,

NRbC (NCN) NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb) , aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2R3, -OCONR6Rc, -OCONRbRc, -OP (O) (ORb) ORc, sulfanyl (such as SRb), sulfinyl (such as -SOR3), and sulfonyl (such as as -SO2Ra and -SO2NR6Rc),

wherein Ra is chosen from optionally substituted C1 -C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

R b is chosen from optionally substituted H, C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R0 is independently chosen from hydrogen and optionally substituted C1 -C4 alkyl; or

Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

wherein each optionally substituted group is unsubstituted or independently substituted by one or more, such as one, two or three substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl- C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2, -C 1 -C 4 alkyl NH 2, -N (C1 -C4 alkyl) (C1 -C4 alkyl), -NH (C1 -C4 alkyl), -N (C1 -C4 alkyl) (C1 -C4 alkylphenyl), -NH (C1 -C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO 2 H, -C (O) OC 1 -C 4 alkyl, -CON (C 1 -C 4 alkyl) (-C 1 -C 4 alkyl), -CONH (C 1 -C 4 alkyl), -CONH 2, -NHC (0) (C 1 -C 4 alkyl), -NHC ( 0) (phenyl), -N (C1 -C4 alkyl) C (0) (C1 -C4 alkyl), -N (C1 -C4 alkyl) C (0) (phenyl), -C (O) C1-C4 alkyl, -C (O) C 1 -C 4 alkylphenyl, -C (O) C 1 -C 4 haloalkyl, -OC (O) C 1 -C 4 alkyl, -SO 2 (C 1 -C 4 alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2, -SO 2 NH (C1 -C4 alkyl), -SO2 NH (phen ila), -NHSO 2 (C 1 -C 4 alkyl), -NHS 2 O (phenyl), and -NHS 2 O (C 1 -C 4 haloalkyl).

In some embodiments, a substituted alkoxy group is "polyalkoxy" or -O- (optionally substituted alkylene) - (optionally substituted alkoxy), and includes groups such as -OCH 2 CH 2 OCH 3, and glycol ether residues such as polyethylene glycol and -O (CH 2 CH 2 O) x CH 3, where χ is an integer of 2-20, such as 2-10, and for example 2-5. Another substituted alkoxy group is hydroxyalkoxy or -OCH 2 (CH 2) y OH, where y is an integer of 1-10, such as 1-4.

The term "alkoxycarbonyl" refers to a group of formula (alkoxy) (C = O) - bonded through carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus, a C1 -C6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.

The term "substituted alkoxycarbonyl" refers to the (substituted alkyl) -OC (O) - group, wherein the group is attached to the precursor structure through carbonyl functionality and where substituted refers to alkyl wherein one or more ( such as up to 5, for example up to 3) hydrogen atoms are substituted by a substituent independently chosen from:

-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NR0CO2Ra, -NRcCONRbRc, -NRbC (NRc) NRbRc, -NRbC (NCN) NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRdR0), -OCORb, -OCO2Ra, -OCONRbRc, -OCONRbR0, OP (O) (ORb) OU0, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NRbRc),

wherein Ra is chosen from optionally substituted C1 -C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

Rb is chosen from H, optionally substituted C1 -C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

Rc is independently chosen from hydrogen and optionally substituted C1 -C4 alkyl; or Rd and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and wherein each optionally substituted group is unsubstituted or independently substituted by one or more, such as one, two or three substituents independently selected from C1 -C4 alkyl, aryl, heteroaryl, aryl C1 -C4 alkyl, heteroaryl C1 -C4 alkyl, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2, -C 1 -C 4 alkyl-NH 2, -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl) ), -NH (C 1 -C 4 alkyl), -NCC 1 -C 4 8yl) CC 1 -C 4 alkylphenyl), -NHCC 1 -C 4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO 2 H, -C ( O) C 1 -C 4 alkyl, -CON (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), -CONHCC 1 -C 4 alkyl), -CONH 2, -NHC (0) (C 1 -C 4 alkyl), -NHC (0) (phenyl), -N (C 1 -C 4 alkyl) ) C (O) (C 1 -C 4 alkyl), -N (C 1 -C 4 alkyl) C (0) (phenyl), -C (O) C 1 -C 4 alkyl, -C (O) C 1 -C 4 alkylphenyl, -C ( O) C 1 -C 4 haloalkyl, -OC (O) C 1 -C 4 alkyl, -SO 2 (C 1 -C 4 alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2, -SO 2 NH (C 1 -C 4 alkyl), -SO 2 NH (phenyl ), -NHS02 (C1 -C4 alkyl), -NHSO2 (phenyl), and -NHS02 (C1 -C4 haloalkyl).

"Acyl" refers to the groups HC (O) -, (alkyl) -C (O) -, (aryl) -C (O) -, (heteroaryl) -C (O) -, and (heterocycloalkyl) -C (O) - wherein the group is attached to the precursor structure through carbonyl functionality, and wherein alkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted as described herein. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. "Lower acyl" refers to groups containing one to six carbons and "acyloxy" refers to the O-acyl group.

The term "amino" refers to the group -NH2.

The term "substituted amino" refers to the group -NHRd or -NRdRe where

Rd is chosen from hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, sulfinyl and sulfonyl

Re is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, and wherein

Substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example up to 3) hydrogen atoms are substituted by one. independently chosen substituent from:

-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC (NRc) NRbRc, -NRbC (NCN) NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OCONRbRc OP (O) (ORb) ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NFcRc), wherein

Ra is chosen from optionally substituted C1 -C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

Rb is chosen from H, optionally substituted C1 -C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

Rc is independently chosen from hydrogen and optionally substituted C1 -C4 alkyl; or Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and wherein each optionally substituted group is unsubstituted or independently substituted by one or more, such as one, two or three substituents independently selected from C1 -C4 alkyl, aryl, heteroaryl, aryl C1 -C4 alkyl, heteroaryl C1 -C4 alkyl -, C 1 -C 4 haloalkyl, - C 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -COCC 4 haloalkyl, halo, -OH, -NH 2, -C 1 -C 4 alkyl-NH 2, -N (C 1 -C 4 alkyl) ( C 1 -C 4 alkyl) -NH (C 1 -C 4 alkyl), -N (C 1 -C 4 alkyl) (C 1 -C 4 alkylphenyl), -NH (C 1 -C 4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C (O) OC1 -C4 alkyl, -CON (C1 -C4 alkyl) (C1 -C4 alkyl), -CONH (C1 -C4 alkyl), -CONH2, -NHC (O) (C1 -C4 alkyl), -NHC (0 ) (phenyl), -N (C1 -C4 alkyl) C (0) (C1 -C4 alkyl), -N (C1 -C4 alkyl) C (0) (phenyl), -C (O) C1-C4 alkyl, -C (O) C1 -C4 alkylphenyl, -C (O) C1 -C4 haloalkyl, -OC (O) C1 -C4 alkyl, -SO2 (C1 -C4 alkyl), -SO2 (phenyl), -SO2 (C1 -C4 haloalkyl), -SO2 NH2, -SO2 NH ( C1 -C4 alkyl), -SO2 NH ( phenyl), -NHSO 2 (C 1 -C 4 alkyl), -NHS 2 O (phenyl), and -NHS 2 O (C 1 -C 4 haloalkyl); and wherein optionally substituted acyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

The term "substituted amino" also refers to N-oxides of the -NHRd, and NRdRd groups each as described above. N-oxides may be prepared from the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with the reaction conditions for performing N-oxidation.

The term "aminocarbonyl" refers to the group -CONRbRc, in

B ·

where R is chosen from H, optionally substituted C1 -C6 alkyl, cycloalkyl

optionally substituted, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

Rc is independently chosen from hydrogen and optionally substituted C1 -C4 alkyl; or

Rb and Rc taken together with the nitrogen to which they are attached form an optionally substituted 5- to 7-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N and S in the heterocycloalkyl ring;

wherein each group is independently substituted by one or more substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl, C 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl -C1 -C4 alkyl-OH, -OC1 -C4 haloalkyl, halo, -OH, -NH2, -C1 -C4 alkyl-NH2, -N (C1 -C4 alkyl) (C1 -C4 alkyl), -NH (C1 -C4 alkyl), -N (C 1 -C 4 alkyl) (C 1 -C 4 alkylphenyl), -NH (C 1 -C 4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO 2 H, -C (O) OC 1 -C 4 alkyl, -CON (C1 -C4 alkyl) (C1 -C4 alkyl), -CONH (C1 -C4 alkyl), -CONH2, -NHC (0) (C1 -C4 alkyl), -NHC (0) (phenyl), -N (C1 -C4 alkyl) C ( O) (C1 -C4 alkyl), -N (C1 -C4 alkyl) C (0) (phenyl), -C (O) C1 -C4 alkyl, -C (O) C1 -C4 alkylphenyl, -C (O) C1 -C4 haloalkyl, -OC (O) C1 -C4 alkyl, -SO2 (C1 -C4 alkyl), -SO2 (phenyl), -SO2 (C1 -C4 haloalkyl), -SO2 NH2, -SO2 NH (C1 -C4 alkyl), -SO2 NH (phenyl), -NSO2 (C1 -C4 alkyl) ), -NHS02 (phenyl), and -NHS02 (C1 -C4 haloalkyl). "Arila" includes:

6-membered carbocyclic aromatic rings, for example

benzene;

bicyclic ring systems where at least one ring is

carbocyclic and aromatic, for example, naphthalene, indane, and tetraline; and

tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example fluorene.

For example, aryl includes 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocyclyl ring containing 1 or more heteroatoms chosen from N, O, and S. For such fused bicyclic ring systems, wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be on the carbocyclic aromatic ring or the heterocycloalkyl ring. Bivalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are called as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals, whose names end in "-yla" by removal of a hydrogen atom from the free valence carbon atom, are designated by adding "-idene" to the name of the corresponding univalent radical, P. For example, a naphthyl group with two bonding points is called naphthylidene. Arila, however, does not in any way encompass or overlap with heteroaryl, separately defined below. Accordingly, if one or more carbocyclic aromatic rings are used with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl as defined herein.

"Aralkoxy" refers to the group -O-aralkyl. Similarly, "heteroaralkoxy" refers to the group -O-heteroaralkyl; "aryloxy" refers to -O-aryl; and "heteroaryloxy" refers to the group -O-heteroaryl. "Aralkyl" refers to a residue in which a component

aryl is attached to the precursor structure via an alkyl residue. Examples include benzyl, phenethyl, phenylvinyl, phenylalyl and the like. "Heteroaralkyl" refers to a residue wherein a heteroaryl component is attached to the precursor structure via an alkyl residue. Examples benzyl, phenethyl, phenylvinyl, phenylalyl and the like. "Heteroaralkyl" refers to a residue and a heteroaryl component is attached to the precursor structure via an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl and the like.

"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Dialoaryl, dialoalkyl, trialoaryl etc. refers to aryl and alkyl substituted by a plurality of halogens, but not necessarily a plurality of the same halogen, so 4-chloro-3-fluorophenyl is within the scope of dialoaryl.

"Heteroaryl" includes: 5- to 7-membered aromatic monocyclic rings containing a

or more, for example from 1 to 4, or in certain embodiments, from 1 to 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;

bicyclic heterocycloalkyl rings containing one or more, for example from 1 to 4 or, in certain embodiments, from 1 to 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and at least a heteroatom is present on an aromatic ring; and

tricyclic heterocycloalkyl rings containing one or more, for example, from 1 to 5 or, in certain embodiments, from 1 to 4 heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least A heteroatom is present in an aromatic ring.

For example, heteroaryl includes a 5-7 membered heterocycloalkyl, aromatic ring fused to a cycloalkyl ring or 5-7 membered heterocycloalkyl. For such fused bicyclic heteroaryl ring systems wherein only one ring contains one or more heteroatoms, the point of attachment may be on one or the other ring. When the total number of atoms S and O of the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms of the heteroaryl group is no more than 2. In certain embodiments, the total number of S and O atoms of the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include but are not limited to (as numbered from the assigned priority 1 binding position), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl , 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, 5,6,7,8-tetrahydroisoquinolinyl. Bivalent radicals derived from univalent heteroaryl radicals, whose names end in "-yla" by removal of a hydrogen atom from the free valence atom, are designated by adding "-idene" to the name of the corresponding univalent radical, e.g. e.g., a two-point pyridyl group is a pyridylidene. Heteroaryl does not encompass or overlap with aryl, cycloalkyl or heterocycloalkyl as defined herein. Substituted heteroaryl also includes ring systems

substituted by one or more oxide (-O ") substituents, such as pyridinyl N-oxides.

By "heterocycloalkyl" we mean a single non-aromatic ring, usually having 3 to 7 ring atoms, containing at least 2 carbon atoms plus 1 - 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, as well as combinations comprising at least one of the preceding heteroatoms. The ring may be saturated or have one or more carbon-carbon double bonds. Suitable heterocycloalkyl groups include, for example (as numbered from the assigned priority binding position 1), 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, and 2, 5-piperizinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered where oxygen is given priority 1). Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo (= O) or oxide (-O ") substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1 dioxo-thiomorpholinyl.

"Heterocycloalkyl" also includes bicyclic ring systems in which a non-aromatic ring, usually 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 independently selected heteroatoms of oxygen, sulfur and nitrogen, as well as combinations comprising at least one of the preceding heteroatoms; and the other ring, usually having 3 to 7 ring atoms, optionally contains 1 - 3 heteroatoms independently selected from oxygen, sulfur and nitrogen and is nonaromatic.

"Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(. ±.)" Is used to denote a racemic mixture where appropriate.

"Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction (dextro or levorotatory). ) wherein they rotate the polarized light in the plane at the wavelength of sodium line D. Certain compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms which can be defined in terms of absolute stereochemistry, such as (R) - or (S) -. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically pure (R) - and (S) - isomers may be prepared using chiral syntones or chiral reagents, or resolved using conventional techniques. Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

"Tautomers" are structurally distinct isomers, which interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-changing tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton accompanied by changes in the binding order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (eg in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol keto tautomerization. A specific example of phenolide tautomerization is the interconversion of pyridin-4-ol and pyridin-4- (1H) -one tautomers. The compounds of formula I and compounds of formula II are tautomeric.

A leaving group or atom is any group or atom that, under the reaction conditions, will cleave from the starting material, thereby promoting the reaction at a specified site. Examples of such groups, unless otherwise specified, are halogen atoms, mesyloxy, p-nitrobenzenesulfonyloxy and tosyloxy groups.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically acceptable substances is well known in the art. Except insofar as any conventional media or people are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

Protecting group has the meaning conventionally associated with it in organic synthesis, that is, a group that selectively blocks one or more reactive sites of a multifunctional compound, so that a chemical reaction can be selectively performed on another unprotected reactive site and so that the group can be promptly removed after the selective reaction is complete. A variety of protecting groups are described, for example, in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a hydroxy protected form is wherein at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.

The term "pharmaceutically acceptable salt" refers to salts that retain the efficacy and biological properties of the compounds described herein and which are not biologically or otherwise undesirable. In many cases, the compounds described herein are capable of forming acid and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. The organic acids from which the salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, puruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases. Inorganic bases from which the salts may be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Organic bases from which the salts may be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like, specifically such as isopropylamine, trimethylamine, diethylamine. triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium and magnesium salts.

The term "solvate" refers to a compound (e.g., a compound selected from Formula I and Formula II, or a pharmaceutically acceptable salt thereof) in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that "a compound of formula I" and "a compound of formula II" comprise the compound of formula I and the compound of formula II and solvates of such compounds, as well as mixtures thereof.

The terms "substituted" alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, unless otherwise expressly defined, refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5 , for example, up to 3) hydrogen atoms are substituted by a substituent independently chosen from:

-Ra, -ORb, optionally substituted amino (including - NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC (NRc) NRbRc, NRbC (NCN) NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbR0), -OCORb, -OCO2Ra, -OCONRbRc, -OCONRbR0, -OPONRbR0 (O) (ORb) ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NRbRc), wherein

Ra is chosen from optionally substituted C1 -C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

Rb is chosen from hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

Rc is independently chosen from hydrogen and optionally substituted C1 -C4 alkyl; or

Rd and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

wherein each optionally substituted group is unsubstituted or independently substituted by one or more, such as one, two or three substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, arylC 1 -C 4 alkyl, teri-C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2, -C 1 -C 4 alkyl-NH 2, -N (C 1 -C 4 alkyl) (C 1 - (C 1 -C 4 alkyl) -NH (C 1 -C 4 alkyl), -N (C 1 -C 4 alkyl) (C 1 -C 4 alkylphenyl), -NHtC 1 -C 4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO 2 H, - C (O) OC 1 -C 4 alkyl, -CONtC 1 -C 4 alkyl (C 1 -C 4 alkyl), -CONH (C 1 -C 4 alkyl), -CONH 2, -NHC (0) (C 1 -C 4 alkyl), -NHC (0) (Cχ-C 4 ( 0) (phenyl), -N (C1 -C4 alkyl) C (0) (C1 -C4 alkyl), -N (C1 -C4 alkyl) C (0) (phenyl), -C (O) C1 -C4 alkyl, -C ( O) C 1 -C 4 alkylphenyl, -C (O) C 1 -C 4 haloalkyl, -OC (O) C 1 -C 4 alkyl, -SO 2 (C 1 -C 4 alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2, -SO 2 NH (C 1 -C 4 alkyl), -SO 2 NH (f enyl), -NHSO 2 (C 1 -C 4 alkyl), -NHS 2 O (phenyl), and -NHS 2 O (C 1 -C 4 haloalkyl).

The term "sulfanyl" refers to the groups: -S- (optionally substituted alkyl), -S- (optionally substituted cycloalkyl), -S- (optionally substituted aryl), -S- (optionally substituted heteroaryl), and -S - (optionally substituted heterocycloalkyl).

The term "sulfinyl" refers to the groups: -S (O) -H, -S (O) - (optionally substituted alkyl), -S (0) - (optionally substituted cycloalkyl), -S (0) - ( optionally substituted amino), -S (O) - (optionally substituted aryl), -S (O) - (optionally substituted heteroaryl), and -S (O) - (optionally substituted heterocycloalkyl).

The term "sulfonyl" refers to the groups: -S (O2) -H, S (O2) - (optionally substituted alkyl), -S (02) - (optionally substituted cycloalkyl), -S (02) - (amino optionally substituted), -S (02) - (optionally substituted aryl), -S (02) - (optionally substituted heteroaryl), and -S (02) - (optionally substituted heterocycloalkyl).

The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound selected from Formula I and Formula IIa which is sufficient to perform the treatment as defined below when administered to a mammal in need of such treatment. The therapeutically effective amount will vary, depending on the subject and condition being treated, the weight and age of the subject, the severity of the condition, the particular selected compound of Formula I and Formula II, the dosage regimen to be followed, time of administration. , the manner of administration and the like, all of which can be readily determined by a person of ordinary skill in the art.

"ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins comprising molecular motors such as myosins.

As used here "frailty" is a syndrome characterized by satisfying three of the following five attributes: unintentional weight loss, muscle weakness, slow walking speed, exhaustion and low physical activity.

As used herein, "cachexia" means a metabolic defect often associated with cancer, which is characterized by progressive weight loss due to deletion of adipose tissue and skeletal muscle.

As used herein, "muscle spasm" means a

involuntary contraction of a muscle. Muscle spasms can result in cramps.

As used herein, "postoperative muscle weakness" refers to a reduction in the resistance of one or more muscles following the surgical procedure. Weakness may be generalized (ie, total body weakness) or localized to a specific area, body side, limb, or muscle.

As used herein, "posttraumatic muscle weakness" refers to a reduction in resistance of one or more muscles following a traumatic episode (eg, bodily injury). Weakness may be generalized (ie, total body weakness) or localized to a specific area, body side, limb, or muscle.

As used herein, "neuromuscular disease" means any disease that affects any part of the nerve and muscle. Neuromuscular disease encompasses chronic disease polyneuropathy, prolonged neuromuscular blockade, acute myopathy as well as acute inflammatory demyelating polyradiculoneuropathy, amyotrophic lateral sclerosis (ALS), autonomic neuropathy. Charcot-Marie-Tooth disease and other hereditary motor and sensory neuropathies, chronic inflammatory demyelating polyradiculoneuropathy, dermatomyositis / polymyositis, diabetic neuropathy, dystrophinopathies, endocrine myopathies, hemifacial spasm, Hereditary Marie-Tooth-like neuropathies , inclusion body myositis, Kennedy's disease, Eaton myasthenic syndrome, muscular dystrophy (eg, waist-limb, Duchenne, Becker, myotonic, facioscapulohumeral, etc.), metabolic myopathies, metabolic neuropathy, motor neuropathy multifocal block with conduction blocks, myasthenia gravis, Friedreich neuropathy Ataxia, leprosy neuropathy, nutritional neuropathy, periodic paralysis, primary lateral sclerosis, restrictive lung disease, sarcoidosis and neuropathy, Schwartz-Jampel syndrome, spinal muscular atrophy, person's syndrome stiffness, thyroid disease, traumatic peripheral nerve injury , vasculitic neuropathy, among others.

As used herein, "obesity" means having a body mass index (BMI) of greater than or equal to 30 kg / m2. BMI is defined as weight (kg) divided by height (m2). Obesity covers hyperplastic obesity, an increase in the number of fat cells and hypertrophic obesity, an increase in the size of fat cells. Overweight is defined as having a BMI of 25 to 30 kg / m2; Obesity as a BMI greater than or equal to 30 kg / m2, as noted above, and Severe (or morbid) obesity is defined as a BMI greater than or equal to 40 kg / m2.

As used herein, "sarcopenia" means a loss of skeletal muscle mass, quality and strength. Sarcopenia is often attributed to aging but is also associated with HIV infection. Sarcopenia can result in frailty, for example in the elderly. As used herein, "wasting syndrome" means a

condition characterized by involuntary weight loss associated with chronic fever and diarrhea. In some instances, patients with wasting syndrome lose 10% of baseline body weight within one month. The compounds of formula I and compounds of formula II also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, as well as your mixtures. "Crystalline form", "polymorph" and "new form" may be used interchangeably herein and include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms, as well as mixtures thereof, unless a crystalline or amorphous form is mentioned.

Chemical entities include but are not limited to compounds of formula I, compounds of formula II and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds cited herein include salts, chelates, non-covalent complexes, pharmaceutically acceptable prodrugs and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Accordingly, the terms "chemical entity" and "chemical entities" also encompass pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs and mixtures.

"Pharmaceutically acceptable salts" include but are not limited to salts with inorganic acids, such as hydrochloride, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate and similar salts; as well as salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC- (CH2) n-COOH where η ranges from 0 to 4, and similar salts. Similarly, pharmaceutically acceptable cations include but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. In addition, if the compound of formula I or the compound of formula II is obtained as an acid addition salt, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to the invention. conventional procedures for preparing acid addition salts of base compounds. Those skilled in the art will recognize various synthetic methodologies which may be used to prepare non-toxic pharmaceutically acceptable addition salts.

As noted above, prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the selected compounds of Formula I and Formula II. The term "prodrug" includes any compound that becomes a compound of Formula I or a compound of Formula II when administered to a patient, e.g. eg in the metabolic processing of the prodrug. Exemplary prodrugs include but are not limited to acetate, formate, benzoate and similar derivatives of functional groups (such alcohol or amine groups) of the selected compounds of Formula I and Formula II.

The term "chelate" refers to the chemical entity formed by the coordination of a compound on a metal ion at two (or more) points.

The term "non-covalent complex" refers to the chemical entity formed by the interaction of a compound and another molecule in which a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding and electrostatic interactions (also called ionic bonding).

The term "active agent" is used to indicate a chemical entity that has biological activity. In certain embodiments, an "active agent" is a compound having pharmaceutical utility.

The term "therapeutically effective amount" of a chemical entity means an effective amount when administered to a human or non-human patient to treat a disease, e.g. e.g., a therapeutically effective amount may be an amount sufficient to treat a myosin activation responsive disease or disorder. The therapeutically effective amount may be verified experimentally, for example by testing the blood concentration of the chemical entity or, theoretically, by calculating bioavailability. By "significant" we mean any change

detectable to be statistically significant in a standard parametric test of statistical significance, such as Studenfs T-test, where ρ <0.05.

"Patient" refers to an animal, such as a mammal, for example, a human, that has been or will be the object of treatment, observation or experiment. The methods described herein may be used in both human and veterinary therapy applications. In both embodiments, the patient is a mammal and in some embodiments, the patient is human.

"Treatment" or "treating" means any treatment of a disease in a patient, including:

(a) avoid the disease, that is, prevent the clinical symptoms of the disease from developing;

(b) inhibit the disease;

(c) slow or halt the development of clinical symptoms;

and / or

(d) relieve disease, that is, cause regression of symptoms

clinical

As used herein, "modulation" refers to a change in one or more of skeletal myosin, skeletal actin, skeletal thromomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T and skeletal muscle, including fragments and isoforms, as well as the skeletal sarcomere as a direct or indirect response to the presence of at least one chemical entity described herein relating to myosin or sarcomere activity in the absence of the compound. The change may be an increase in activity (potentiation) or a decrease in activity (inhibition) and may be due to the direct interaction of the compound with the myosin or sarcomere, or due to the interaction of the compound with one or more other factors which, for example. in turn perform one or more of skeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T and skeletal muscle, including fragments and isoforms, as well as the skeletal sarcomere.

At least one chemical entity chosen from the compounds of formula I and compounds of formula II is provided:

Formula I Formula II

and pharmaceutically acceptable salts thereof, wherein R 1 and R 4 are independently selected from hydrogen, halo, hydroxy, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, alkoxy optionally substituted, optionally substituted aminocarbonyl, sulfonyl, sulfanyl, sulfinyl, carboxy, optionally substituted alkoxycarbonyl, and cyano; and, alternatively, R4 and R1, taken together with any intervening atoms, form a fused ring system selected from optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused cycloalkyl, and optionally substituted fused heterocycloalkyl; and

R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;

since

R1 is not hex-1-enyl; and provided that the compound of Formula I or the compound of Formula II is not (S) -6-bromo-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

one;

1,5,6-trimethyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1-methyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

6-bromo-1- (3-nitrobenzyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

one;

5- (hydroxymethyl) -1,6-dimethyl-1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one; or

1- (piperidin-4-yl) -1H-imidazo [4,5-b 3 pyrazin-2 (3H) -one.

In some embodiments, R 2 is selected from optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, and optionally substituted heterocycloalkyl.

In some embodiments, R 2 is selected from heterocycloalkyl, cycloalkyl, lower alkyl, and optionally substituted phenyl substituted hydroxy, optionally substituted alkoxy, optionally substituted amino and optionally substituted heterocycloalkyl.

In some embodiments, R 2 is selected from I- (R) -phenylethyl, I- (S) -phenylethyl, benzyl, 3-pentyl, 4-heptyl, 4-methyl-1-morpholinopentan-2-yl isobutyl, cyclohexyl , cyclopropyl, sec-butyl, tert-butyl, isopropyl, 1-hydroxybutan-2-yl, tetrahydro-2H-pyran-4-yl, 1-methoxybutan-2-yl, 1-aminobutan-2-yl, and 1- morpholinobutan-2-yl.

In some embodiments, R1 is selected from hydrogen, halo, acyl, optionally substituted lower alkyl, optionally substituted amino, optionally substituted pyrazolyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted lower alkoxy, and -S- (lower alkyl). optionally substituted).

In some embodiments, R 1 is selected from hydrogen, halo, acyl, optionally substituted lower alkyl, dialkylamino, amino substituted by an alkyl group and a group selected from acyl, aminocarbonyl, alkoxycarbonyl, and sulfonyl; optionally substituted pyrazolyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted lower alkoxy, and -S- (optionally substituted lower alkyl).

In some embodiments, R 1 is selected from hydrogen, halo, acyl, alkenyl, alkynyl, lower alkoxy, optionally substituted amino, lower alkyl substituted pyrazolyl, -S- (optionally substituted lower alkyl), lower alkyl, and substituted lower alkyl by halo.

In some embodiments, R 1 is selected from hydrogen, halo, acyl, alkenyl, alkynyl, lower alkoxy, dialkylamino, amino substituted by an alkyl group and a group selected from acyl, aminocarbonyl, alkoxycarbonyl, and sulfonyl, alkyl substituted pyrazolyl lower, -S- (optionally substituted lower alkyl), lower alkyl, and halo substituted lower alkyl.

In some embodiments, R 1 is selected from hydrogen, bromine, chlorine, fluoro, methyl, ethyl, propyl, hexenyl, butenyl, propenyl, vinyl, ethinyl, methoxy, ethoxy, methylsulfanyl, dimethylamino, and methyl substituted with one to three. Fluoro groups.

In some embodiments, R 1 is selected from hydrogen, bromine, chlorine, fluoro, methyl, ethyl, n-propyl, isopropyl, dimethylamino, isobuten-1-yl, (Z) -propen-i-yl, (E) - propen-1-yl, propen-2-yl, vinyl, ethynyl, methoxy, ethoxy, methylsulfanyl, and trifluoromethyl.

In some embodiments, R 4 is selected from hydrogen, halo, acyl, optionally substituted alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, sulfanyl, optionally substituted amino, and optionally substituted alkoxycarbonyl.

In some embodiments, R 4 is selected from optionally substituted hydrogen, halo, acyl, lower alkyl, lower alkenyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, sulfanyl, optionally substituted amino, and optionally substituted lower alkoxycarbonyl.

In some embodiments, 14 is selected from hydrogen, halo, acyl, lower alkyl, lower alkenyl, cycloalkyl, optionally substituted aminocarbonyl, sulfanyl, and lower alkoxycarbonyl.

In some embodiments, R 4 is selected from hydrogen, bromine, chlorine, fluoro, acetyl, methyl, ethyl, vinyl, cyclohexen-1-yl, methylcarbamoyl, dimethylcarbamoyl, methylsulfanyl, and methoxycarbonyl.

In some embodiments, R4 is hydrogen.

In some embodiments, R4 and Rb taken together with any intervening atoms form a fused ring system selected from optionally substituted fused aryl, optionally substituted fused cycloalkyl, and optionally substituted fused heterocycloalkyl.

In some embodiments, R 4 and R 4 are taken together to form an optionally substituted benzo group.

In some embodiments, R 4 and R 1 are taken together to form a benzo group.

In some embodiments, the compound of Formula I is

chosen from

1 - ((1R) -1-methyl-2-morpholin-4-ylethyl) -6-bromoimidazo [4,5-

b] pyrazin-2-ol;

1- (ethylpropyl) -6-ethynylimidazo [4,5-b] pyrazin-2-ol; 1- (ethylpropyl) -6-methoxyimidazo [4,5-b] pyrazin-2-ol; 1- (1,1-dimethyl-2-morpholin-4-ylethyl) -6-bromoimidazo [4,5-

b] pyrazin-2-ol;

6- (1H-1,2,3-triazol-4-yl) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-1-one

2-ol;

1- (ethylpropyl) -6- (trifluoromethyl) imidazo [4,5-b] pyrazin-2-ol; 1 - [(1R) -1- (morpholin-4-ylmethyl) propyl] -6-ethynylimidazo [4,5-

b] pyrazin-2-ol;

1- (ethylpropyl) -6- {2- [1- (ethylpropyl) -2-hydroxyimidazo [4,5- e] pyrazin-6-yl] ethynyl} imidazo [4,5-b] pyrazin-2-ol;

6- (dimethylamino) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol; 6-ethyl-1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol;

(E) -1- (pentan-3-yl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2-ol;

(E) -1-cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (E) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

ol;

(E) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (E) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol;

(R) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

(R) -6-bromo-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

(R) -6-Bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

(R) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (4-methylpiperazin-1-yl) methanone;

(S) - (2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-6-yl) (morpholino) methanone;

(S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (piperidin-1-yl) methanone;

(S) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1- (1-phenylethyl) -1H-imidazo [4,5-b] qoxoxalin-2-ol; (S) -1- (1-phenylethyl) -6- (piperidin-1-ylmethyl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

(S) -1- (1-phenylethyl) -6-propyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1- (1-phenylethyl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1 - (2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-6-one

ila) ethanone;

(S) -2-Hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-one

carbonitrile;

(S) -2-Hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-one

carboxamide;

r

(S) -2-Hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazinecarboxylic acid

6-carboxylic acid;

(S) -2-hydroxy-N, N-dimethyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carboxamide;

(S) -2-hydroxy-N-methyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide;

(S) -6 - ((4-methylpiperazin-1-yl) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol;

(S) -6 - ((dimethylamino) methyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-

b] pyrazin-2-ol;

(S) -6- (2-hydroxypropan-2-yl) -1- (1-phenylethyl) -1 H -imidazo [4,5-

b] pyrazin-2-ol;

(S) -6- (2-methylprop-1-enyl) -1- (1-phenylethyl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

(S) -6- (methylsulfonyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2-ol;

(S) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6- (morpholinomethyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-

b] pyrazin-2-ol;

(S) -6-Bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

(S) -6-bromo-1- (1-morpholinobutan-2-yl) -1 H -imidazo [4,5-

b] pyrazin-2-ol;

(S) -6-bromo-1- (1-morpholinopropan-2-yl) -1 H -imidazo [4,5-

b] pyrazin-2-ol;

(S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-cyclohexenyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-one

ol;

(S) -6-cyclohexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-ethoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-ethyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-hexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Isobutyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Methoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -methyl 2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-1-one

6-carboxylate;

(S) -N, N-diethyl-2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide;

(S) -N-benzyl-2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide; (SJE) -1- (1-phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2-ol;

(S, Z) -1- (1-phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2-ol;

(S, Z) -6- (hex-2-enyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-one

2-ol;

(Z) -1- (pentan-3-yl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

2-ol;

(Z) -1-cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (Z) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

ol;

(Z) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (Z) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol;

1- (1-aminobutan-2-yl) -6-bromo-1H-imidazo [4,5-b] pyrazin-2-one

ol;

1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-blpyrazin-2-yl; 1- (2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-5-one

il) ethanone;

1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-2,6-diol;

1- (pentan-3-yl) -1H-imidazo [4,5-b] quinoxalin-2-ol;

1- (pentan-3-yl) -5-vinyl-1H-imidazo [4,5-b] pyrazin-2-ol;

1- (pentan-3-yl) -6- (prop-1-ynyl) -1H-imidazo [4,5-b] pyrazin-2-ol;

1- (pentan-3-yl) -6- (trifluoromethyl) -1H-imidazo [4,5-b] pyrazin-2-ol;

1-benzyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol;

1-benzyl-6-bromo-1H-imidazo [4,5-b] pyrazin-2-ol;

1-cyclohexyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol;

1-cyclopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol;

1-isopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol;

2- (6-bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) -1-morpholinobutan-1-one;

2- (6-Bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl acid)

butanoic;

2- (6-bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) propane-1,3-diol;

r

2-Hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-acid

carboxylic acid;

2-hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-6-one

carbonitrile;

2-hydroxy-N, N-dimethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxamide;

2-hydroxy-N-methyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxamide;

5- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 5-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol;

5-ethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol;

6- (methylsulfinyl) -1 - ((S) -1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2-ol; 6- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 6- (methylthio) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

6-bromo-1- (1- (4- (methylsulfonyl) piperazin-1-yl) butan-2-yl) -1H imidazo [4,5-b] pyrazin-2-ol;

6-bromo-1- (1- (4-methylpiperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol;

6-bromo-1- (1- (dimethylamino) butan-2-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol;

6-bromo-1- (1- (methylamino) butan-2-yl) -1H-imidazo [4-15-

b] pyrazin-2-ol;

6-bromo-1- (1-methoxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 6-bromo-1- (2-methyl-1-morpholinopropan-2-yl) -1 H -imidazo [4,5-

b] pyrazin-2-ol;

6-bromo-1- (2-morpholinoethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 6-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-one

ol;

6-bromo-1-cycloexyl-1H-imidazo [4,5-b] pyrazin-2-ol; 6-bromo-1-cyclopropyl-1H-imidazo [4,5-b] pyrazin-2-ol; 6-bromo-1-isopropyl-1H-imidazo [4,5-b] pyrazm-2-ol; 6-bromo-1-tert-butyl-1H-imidazo [4,5-b] pyrazin-2-ol; 6-cyclopropyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; 6-methoxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2-ol; 6-methyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; methyl 2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazine-5

carboxylate;

methyl 4- (2- (6-bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) butyl) piperazine-1-carboxylate;

1- (ethylpropyl) -6- (1-methylpyrazol-4-yl) imidazo [4,5-b] pyrazin-2-ol; 6-bromo-1- (propylbutyl) imidazo [4,5-b] pyrazin-2-ol; 1 - [(1 R) -3-methyl-1- (morpholin-4-ylmethyl) butyl] -6-bromoimidazo [4,5-b] pyrazin-2-ol;

1- (ethylpropyl) -6-vinylimidazo [4,5-b] pyrazin-2-ol; 1- (ethylpropyl) -6- (1-methylvinyl) imidazo [4,5-b] pyrazin-2-ol; 1- (ethylpropyl) -6- (methylethyl) imidazo [4,5-b] pyrazin-2-ol; 6-chloro-1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol; and 6- (dimethylamino) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol. In some embodiments, the compound of Formula II is chosen from the following tautomers of the compounds of formula I:

(R) -6-bromo-1- (1-morpholinopropan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-methoxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1- (2-methyl-1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1- (pentan-3-yl) -6- (1H-1,2,3-triazol-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1- (pentan-3-yl) -6- (trifluoromethyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

(R) -6-Ethynyl-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

6 - ((2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-6-one)

yl) ethinyl) -1-

(pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6- (dimethylamino) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one; 6-ethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (E) -1- (pentan-3-yl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

(E) -1-Cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

2 (3H) -one;

(E) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

2 (3H) -one;

(E) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

2 (3H) -one;

(E) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(R) -6- (methylthio) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

(R) -6-bromo-1- (1-hydroxybutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one;

(R) -6-bromo-1- (1-morpholinobutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

(R) -6-bromo-1- (1-morpholinopropan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

(R) -6-Bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

(R) -6-Bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one (S) -1- (1-phenylethyl) -1H-imidazo [4 , 5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] quinoxalin-2 (3H) -one; (S) -1- (1-phenylethyl) -6- (piperidin-1-ylmethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -1- (1-phenylethyl) -6- (piperidino-1-carbonyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -1- (1-phenylethyl) -6-propyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -1- (1-phenylethyl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

(S) -2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carbonitrile;

(S) -2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide;

(S) -2-Oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxylic acid;

(S) -6 - ((4-methylpiperazin-1-yl) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6 - ((dimethylamino) methyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-

b] pyrazin-

b] pyrazin-

2 (3H) -one;

(S) -6- (2-hydroxypropan-2-yl) -1- (1-phenylethyl) -1 H -imidazo [4,5-2 (3H) -one;

(S) -6- (2-methylprop-1-enyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-

b] pyrazin-

2 (3H) -one;

(S) -6- (4-methylpiperazine-1-carbonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6- (methylsulfonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

(S) -6- (methylthio) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-one

2 (3H) -one;

(S) -6- (morpholino-4-carbonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6- (morpholinomethyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6-Acetyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

(S) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6-bromo-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6-bromo-1- (1-morpholinopropan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

(S) -6-bromo-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

one;

one;

one;

one;

one;

one;

one;

(S) -6-bromo-1-sec-b) -thyl-1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-cyclohexenyl-1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

(S) -6-Cyclohexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

(S) -6-ethoxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

(S) -6-ethyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-bexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

(S) -6-Isobutyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

(S) -6-Methoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3 H) -

(S) -methyl 2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxylate;

(S) -N, N-diethyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; (S) -N, N-Dimethyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H

imidazo [4,5-b] pyrazine-5-carboxamide;

(S) -N-benzyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; (S) -N-Methyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-

b] pyrazine-5-carboxamide;

(S, E) -1- (1-phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

(S, Z) -1- (1-phenylethyl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-one

(S, Z) -6- (hex-2-enyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-one

(Z) -1- (pentan-3-yl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

(Z) -1-cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

(Z) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

(Z) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-one

(Z) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1- (1-aminobutan-2-yl) -6-bromo-1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

1- (1-morpholinobutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

one;

1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 1- (pentan-3-yl) -1H-imidazo [4,5-b] quinoxalin-2 (3H) -one; 1- (pentan-3-yl) -5-vinyl-1H-imdazo [4,5-b] pyrazin-2 (3H) -one;

2 (3H) -one; 2 (3H) -one; 2 (3H) -one; 2 (3H) -one;

15

2 (3H) -one; 2 (3H) -one; 2 (3H) -one; 1- (pentan-3-yl) -6- (prop-1-ynyl) -1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

1- (pentan-3-yl) -6- (trifluoromethyl) -1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

1-benzyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1-benzyl-6-bromo-1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1-cyclohexyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1-cyclopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

1-isopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

2- (6-Bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyrazin-1-yl) butanoic acid;

2-Oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-

b] pyrazine-5-carboxylic acid; 2-oxo-3- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-one

carbonitrile;

5- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

5-acetyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 5-bromo-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

5-ethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

6- (methylsulfmyl) -1 - ((S) -1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

O- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

6- (methylthio) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

6-bromo-1- (1- (4- (methylsulfonyl) piperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1- (1- (4-methylpiperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3 H) -one;

6-bromo-1- (1- (dimethylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1- (1- (methylamino) butan-2-yl) -1H-imidazo [4,5-

b] pyrazin-2 (3H) -one;

6-bromo-1- (1,3-dihydroxypropan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one;

6-bromo-1- (1-methoxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-one

2 (3H) -one;

6-bromo-1- (1-morpholine-1-oxobutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

6-bromo-1- (2-methyl-1-morpholinopropan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one;

6-bromo-1- (2-morpholinoethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -

one;

6-bromo-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

6-bromo-1-cyclohexyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

6-bromo-1-cyclopropyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1-isopropyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-bromo-1-tert-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-cyclopropyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

6-methoxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 6-methyl-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; methyl 2-oxo-1- (pentan-3-yl) -2,3-dihydro-1 H -imidazo [4,5-

b] pyrazine-5-carboxylate;

methyl 4- (2- (6-bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-

b] pyrazin-1-yl) butyl) piperazine-1-carboxylate;

N.N-dimethyl-2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide;

N-methyl-2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; 6- (1-methyl-1H-pyrazol-4-yl) -1- (pentan-3-yl) -1H-imidazo [4,5-

b] pyrazin-2 (3H) -one;

6-bromo-1- (heptan-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6-bromo-1- (4-methyl-1-morpholinopentan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 1- (pentan-3-yl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one;

1- (pentan-3-yl) -6- (prop-1-en-2-yl) -1 H -imidazo [4,5-b] pyrazin-1-one

2 (3H) -one;

6-isopropyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -

one;

6-chloro-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; and

6- (dimethylamino) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-1-one

2 (3H) -one.

Compounds of formula I may be designated and numbered (e.g. using NamExpert ™ available from Cheminnovation or the ChemDraw Ultra version 10.0 automatic designation feature of Cambridge Sofl Corporation) as described below. For example, compound ie, the compound according to formula I wherein R 1 is (E) -propen-1-yl, R 2 is (S) -sec-phenethyl, and R 4 is H may be designated (S, E) -1- (1-phenylethyl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol. Also the compound:

ie, the compound according to formula I wherein R1 is (Z) -propen-1-yl, R2 is 3-pentyl, and R4 is H may be designated (Z) -1- (pentan-3-yl). ) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol.

Similarly, the compounds of formula IIa may be designated and numbered (e.g., using NamExpert ™ available from Cheminnovation or the automatic name assignment feature).

ChemDraw Ultra version 10.0 from Cambridge Soft Corporation) as described below.

For example, the compound:

ie, the compound according to formula IIa wherein R 1 is (E) -propen-1-yl, R 2 is (S) -sec-phenethyl, and R 4 is H may be designated (S 5 E) -I- (1 - phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one. Also the compound:

ie, the compound according to formula IIa wherein R1 is (Z) -propen-1-yl, R2 is 3-pentyl, and R4 is H may be designated (Z) -1- (pentan-3-yl). ) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one. The chemical entities described herein may be synthesized using techniques well known in the art, e.g. as illustrated below with reference to the Reaction Schemes.

Unless otherwise specified, the reactions described herein occur at atmospheric pressure, generally within a temperature range of -10 ° C to 200 ° C. In addition, except as used in the Examples or as otherwise specified, reaction times and conditions are approximate, e.g. e.g. occurring around atmospheric pressure within a temperature range of from about -10 ° C to about 110 ° C over a period of about 1 to about 24 hours; the reactions left to take place at night span a period of about 16 hours.

The terms "solvent", "organic solvent" and "inert solvent" mean an inert solvent under the reaction conditions being described together with them [including, for example, benzene, toluene, acetonitrile, tetrahydrofiirane ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine and the like]. Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents. Unless otherwise specified, for each gram of limiting reagent, one cc (or ml) of solvent constitutes an equivalent volume.

Isolation and purification of the chemical entities and intermediates described herein may be performed, if desired, by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures may be obtained by reference to the examples below. However, other separation or isolation procedures may also be used.

Where desired, the (R) and (S) isomers may be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which may be separated, for example by crystallization; via formation of diastereoisomeric derivatives, which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer by a specific enantiomer reagent, for example oxidation or enzymatic reduction, followed by separation of unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as ordinary bound chiral ligand silica or in the presence of a chiral solvent. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation.

Many of the optionally substituted starting compounds and other reagents are commercially available, e.g., from the Aldrich Chemical Company (Milwaukee, WI) or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.

Reaction Scheme 1

With reference to Scheme 1, Step 1, in a compound of formula 101, wherein X is halo, an excess (such as about 2 to 20 equivalents) of a compound of formula R2-NH2 is added. The reaction vessel is heated at about 110 ° C to 190 ° C for about 20 to 40 minutes, optionally with microwave irradiation. The product, a compound of formula 102, is isolated and optionally purified. With reference to Reaction Scheme 1, Step 2, in a solution of a compound of formula 102 in a suitable solvent (such as THF) is added a deactivated carbonyl equivalent such as carbonyl dimidazole (CDI), phosgene or triphosgene. The product, a compound of formula 103, is isolated and optionally purified.

Reaction Scheme 2

R2 R9

201 2 104 2

Reaction Scheme 2 illustrates reactions for further converting compounds of Formula 201, wherein X is a leaving group, to compounds of Formula 104 by one of Steps 3 (a-e). In some embodiments, X is halo, for example bromine.

With reference to Reaction Scheme 2, Step 3 (a), a compound of formula 201 and about 0.05 to 0.15 equivalent of a suitable catalyst such as (F3P) 4Pd in a suitable solvent such as NMP or dioxane, a suitable base and an excess (such as about 1.5 to 32 molar equivalents) of a suitable tin reagent such as RiSn (butyl) 3 is mixed at from about 0 to about 200 ° C for about 6 to 48 hours. The product, a compound of formula 104, wherein R x is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl, is isolated and optionally purified.

With reference to Reaction Scheme 2, Step 3 (b), a compound of formula 201 and an excess (such as about 4 to 5 equivalents) of a compound of formula NaSRx, where SRx is an excess (such as about 4-5 equivalents) of a compound of formula NaSRx wherein SRx is R1, and a suitable sulfur (such as NMP) are heated at about 50 ° C to 200 ° C for about 10 min to 24 h, optionally with microwave irradiation. . The product, a compound of formula 104, wherein R 1 is sulfanyl, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 3 (c), a compound of formula 201, an excess (such as about 1.90 to 2.3 equivalents) of a compound of formula RiB (OH) 2, about 0 0.10 to 0.15 equivalent of (DPPF) PdCl2, a suitable solvent (such as dioxane) and about 2 to 3 equivalents of a suitable base (such as 2N K2COs) are heated to about 90 ° C for about 6 to 24 hours. The product, a compound of formula 104, wherein R 1 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl, is isolated and optionally purified.

With reference to Reaction Scheme 2, Step 3 (d), about 2 equivalents of RxOH, where ORx is Rb and a suitable solvent (such as NMP) and about 2 equivalents of suitable base (such as NaH) are added. followed by a compound of formula 201. The mixture is heated to about 50 to about 200 ° C for about 10 minutes to about 48 hours. In some embodiments, the reaction is heated for about 30 minutes, optionally with microwave irradiation. The product, a compound of formula 104, wherein R 1 is optionally substituted alkoxy, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step (e), a compound of formula 201, an excess (such as about 2.0 equivalents) of a compound of formula KR1BF3, an excess (such as about 3 equivalents) of a Suitable base (such as Cs2CO3), a suitable amount of (DPPF) PdCl2 (such as about 0.2 equivalents), a suitable solvent (such as dioxane and water) are mixed at about room temperature to about 100 ° C per about 8 to 48 hours and the product, a compound of formula 104, wherein R 1 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl, is isolated and optionally purified.

A racemic mixture is optionally placed on a chromatography column and separated into (R) - and (S) - enantiomers.

The compounds described herein are optionally contacted by a pharmaceutically acceptable acid to form the corresponding acid addition salts.

Pharmaceutically acceptable acid addition salts of the compounds of formula I or compounds of formula II are optionally contacted by a base to form the corresponding free base.

The chemical entities described herein modulate one or more of skeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T and skeletal muscle, including fragments and isoforms, as well as skeletal sarcomere, and are useful for bind to, inhibit and / or enhance their activity. As used in this context, "modulating" means increasing or decreasing misona activity, while "boosting" means increasing activity and "inhibiting" means decreasing activity.

The chemical entities, pharmaceutical compositions and methods described herein are used to treat obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, post-surgical and post-traumatic muscle weakness, neuromuscular disease and other indications in a mammal.

Methods for identifying chemical entities as binding to a protein or as a modulator of the binding characteristics or biological activity of a protein are described, for example, in U.S. Patent Nos. 6,410,254 and U.S. 10 / 987,165.

For example, test compounds may be assayed in a highly parallel manner by using multiwell plates by placing the compounds individually in wells or by testing them in mixtures. Assay components, including the target protein complex, coupling enzymes and substrates, and ATP can then be added to the wells and the absorbance or fluorescence of each plate well can be measured with a plate reader.

In some embodiments, the method utilizes a 384-well plate format and a reaction volume of 25 μΐ. A pyruvate kinase / lactate dehydrogenase coupled enzyme system (Huang TG and Hackney D. D. (1994) J Biol Chem 269 (23): 16493-501) can be used to measure the rate of ATP hydrolysis in each well. As will be appreciated by those in the art, assay components are added in buffers and reagents. Incubation periods can be optimized to provide adequate detection signals during the experiment. The assay can be performed in real time, providing ATP hydrolysis kinetics that increase the signal to noise ratio of the assay.

The compounds may be further tested using sliced muscle fiber preparations. Such assays are known in the art. See e.g. Cheung et al. (2002) Nature Cell Biol. 4:83 and U.S. Patent Publication No. 20020006962.

The chemical entities described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the aforementioned disease states. Although human dosage levels have yet to be optimized for the chemical entities described herein, generally a daily dosage range of about 0.05 to 100 mg / kg body weight; in certain embodiments from about 0.10 to 10.00 mg / kg body weight and in certain embodiments from about 0.15 to 1.0 mg / kg body weight. Thus, for administration to a 70 kg person in certain embodiments, the dosage range would be about 3.5 to 7000 mg per day; in certain embodiments, from about 7.0 to 700.0 mg per day, and in certain embodiments, about 10.0 to 100.0 mg per day. The amount of the chemical entity administered will, of course, be dependent upon the individual and the ill condition being treated, the severity of the affliction, the manner and program of administration, and the judgment of the prescribing physician: for example, a likely dose range for oral administration would be about 70 to 700 mg per day, whereas for intravenous administration a likely dose range would be about 70 to 700 mg per day, depending on the pharmacokinetics of the compound.

Administration of the chemical entities described herein may be via any of the accepted modes of administration for agents that are employed in similar utilities, including but not limited to oral, sublingual, subcutaneous, intravenous, intranasal, topically, transdermal, intraperitoneal, intramuscular, intrapulmonary. , vaginally, rectally or intraocularly. In some embodiments, oral or parenteral administration is used.

Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. Chemical entities may also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal patches (including electrotransport) and the like, for prolonged and / or regulated pulsed administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

The chemical entities described herein may be administered alone or more typically in combination with a conventional pharmaceutical carrier, excipient or similar (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose , gelatin, sucrose, magnesium carbonate and the like). If desired, the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g. sodium acetate, sodium citrate, derivatives cyclodextrin, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate and the like). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, 0.5% to 50% by weight of a chemical entity. Current methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

In addition, the chemical entities described herein may be co-administered with, and the pharmaceutical compositions may include, other medicinal agents, pharmaceutical agents, adjuvants and the like. Suitable medicinal and pharmaceutical agents include modulators of one or more skeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I and skeletal muscle, including fragments and isoforms thereof, and skeletal sarcomere and other therapeutic agents suitable in the treatment of the above disorders including: anti-obesity agents, anti-sarcopenia agents, anti-wasting syndrome agents, anti-frailty agents, anti-cachexia agents, anti-muscle spasm agents, muscle weakness agents post-surgical and post-traumatic and anti-neuromuscular disease agents, as well as the agents described in US Patent Application No. 2005/0197367.

Suitable additional medicinal and pharmaceutical agents include, for example: orlistat, sibramine, diethylpropion, phentgermine, benzafetamine, phendimetrazine, estrogen, estradiol, levonorgestrel, norethindrone acetate, estradiol valerate, ethinyl estradiol, norgestimate, conjugated estrogens, estrogens, estrogens medroxyprogesterone, testosterone, insulin-derived growth factor, human growth hormone, riluzole, cannabidiol, prednisone, albuterol, non-steroidal anti-inflammatory drugs and botulinum toxin.

Other suitable medicinal and pharmaceutical agents include TRH, diethylstilbesterol, theophylline, encephalins, E series prostaglandins, compounds described in US Patent No. 3,239,345 (e.g., zeranol), compounds described in US Patent No. 4,036,979 (e.g. sulbenox), peptides described in US Patent No. 4,411,890, growth hormone secretagogues such as GHRP-6, GHRP-I (described in US Patent No. 4,411,890 and publications WO 89/07110 and WO 89/07111), GHRP-2 (described in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920 hormone releasing factor. growth hormone and its analogues, growth hormone and its analogues and somatomedines including IGF-I and IGF-2, alpha-adrenergic agonists such as clonidine or serotonin 5-HTD agonists such as sumatriptan, agents that inhibit somatostatin or its release such as physostigmine, pyridostigmine, parathyroid hormone, PTH (1-34) and bisphosphonat such as MD-217 (alendronate).

Still other suitable medicinal and pharmaceutical agents include estrogen, testosterone, selective estrogen receptor modulators such as tamoxifen or raloxifene, other androgen receptor modulators such as those described in Edwards, J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med. Chem., 42, 210-212 (1999), and progesterone receptor ("PRA") agonists such as levonorgestrel, medroxyprogesterone acetate (MPA).

Still other suitable medicinal and pharmaceutical agents include aP2 inhibitors such as those described in US Ser. No. 09 / 519,079, filed March 6, 2000, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists such as AJ9677 (Takeda / Dainippon), L750355 (Merck), or CP331648 (Pfizer), other beta 3 agonists as described in US Pat. 5,541,204, 5,770,615, 5,491,134, 5,777,983 and 5,488,064, a lipase inhibitor such as orlistat or ATL-962 (Alixima), a serotonin (and dopamine) reabsorption inhibitor such as sibutramine , topiramate (Johnson & Johnson) or axokine (Regeneron), a beta thyroid receptor drug, such as a thyroid receptor ligand, as described in WO 97/21993, WO 99/00353, and GB98 / 284425, and anorexic agents , such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.

Still other suitable medicinal and pharmaceutical agents include HIV and AIDS therapies such as indinavir sulfate, saquinavir, saquinavir mesylate, rotonavir, lamivudine, zidovudine, lamivudine / zidovudine combinations, zalcitabine, didanosine, stavudine and megestrol acetate.

Still other suitable medicinal and pharmaceutical agents include anti-resorptive agents, hormone replacement therapies, vitamin D analogues, elemental calcium and calcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectin receptor antagonists, Src SH.sub antagonists. 2, -H + -ATPase inhibitors, ipriflavone, fluoride, Tibolone, pro-stanoids, 17-beta-hydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.

The above and other therapeutic agents, when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. . In certain embodiments, the compositions have taken the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.

Liquid pharmaceutically administrable compositions may, for example, be prepared by dissolving, dispersing etc. at least one chemical entity and optional pharmaceutical adjuvants in a vehicle (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables may be prepared in conventional forms, such as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent upon their specific nature as well as the activity of the chemical entities and the needs of the individual. However, active ingredient percentages of 0.01% to 10% in solution are employable and will be higher if the composition is a solid which will subsequently be diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution.

Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or nebulizer solution, or as a microfine insufflation powder, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition have diameters smaller than 50 microns, in certain embodiments smaller than 10 microns.

The following examples serve to more fully describe the manner of using the invention described above. It is understood that these examples are in no way intended to limit the true scope of this invention, but are no doubt presented for illustrative purposes.

Example 1

Synthesis of (S) -6-Bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol

NH2 / N. NH2

^ N NH 2 J f

χ X _Me 'Ph ΒΛΝΛνη

Br N Br MW, 180 ° C X

Mev ph

Step 1: (S) -6-Bromo-N2- (1-phenylethyl) pyrazine-2,3-diamine.

A thick-walled microwave flask equipped with a stir bar

was loaded with 1.0 equiv of 3,5-dibromopyrazin-2-amine and 6.6 equiv of

(S) -sec-phenethylamine. The flask was fitted with a septum and cap and heated

at 180 ° C in a microwave for 30 min. The resulting solution was adsorbed.

about 20 g of silica; flash vapor chromatography (10% - 50%

EtOAc / Hexanes) provided the title compound (60%) as a non-foamed foam.

totally white. LCMS m / z (APCI) = 293.295.0 (M + H).

N3 / NH2 Nv

CDExcess Jl Br N NH - ^ Brx ^ N N

»THF, 67 ° C Ov ^ Ph

Mex ph me

Step 2: (S) -6-Bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-yl. To a solution of (S) -6-bromo-N2- (1-phenylethyl) pyrazine-2,3-diamine (1.0 equiv) in refluxing anhydrous THF (5 volume equivalents) was added carbonyldiimidazole (CDI). Successive portions of CDI were added until starting material was consumed (approximately total 3.6 equiv.) As judged by TLC (50% EtOC / Hexanes). After complete reaction, the mixture was cooled to room temperature and quenched by the careful addition of water until gas evolution ceased. The mixture was diluted with equivalent volumes of EtOAc and washed with 3 χ 7.5 equivalent volumes of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 5% - 40% EtOAc / Hexanes) provided the title compound (66%) as a solid solid. LCMS m / z (APCI) = 319.0, 321.0 (M + H).

Example 1 (a)

/ n ^ N ^ Sn (O-Bu) 3 / n ^ N

A-Ph Et 3 N, Dioxane Me A Ph

Me 80 0C Me

(S) -1- (2-Hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-6-yl) ethanone. An oven-dried scintillation vial equipped with a stir bar was charged with (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol (1 , 0 equiv), and (F3P) 4Pd (0.07 equiv). The flask was covered with a Parafilm slide and purged with nitrogen for 5 min and anhydrous dioxane (13 volume equivalents), triethylamine (3.0 equiv.) And tributyl (1-ethoxyvinyl) stanane (1.5 equiv) were added. by syringe. The resulting mixture was heated at 80 ° C overnight. The reaction was quenched with 1 N KHSO 4 and stirred for 30 min. The mixture was then diluted with EtOAc, washed twice with NaHCO 3 and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 10% - 86% EtOAc / Hexanes) provided the title compound (33%) as a white solid. LCMS m / z (APCI) = 283.1 (M + H).

Example l (b)

A - Ph Et3N, MW A - Ph

Me NMP, 120 ° C Me °

(S, E) -1- (1-Phenylethyl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-yl. A thick-walled microwave flask equipped with a stir bar was charged with (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol (1, 0 equiv) and (F3P) 4Pd (0.12 equiv). The flask was covered by a Parafilm slide and purged with nitrogen for 5 min, and N-methylpyrrolidone (14 volume equivalents), triethyl amine (2.0 equiv) and (E) -tributiyl (prop-1-enyl) stanane (3.0 equiv ) were added by syringe. The resulting mixture was immediately fitted with a septum and lid and heated to 120 ° C in a microwave for 20 min. The reaction was then diluted with EtOAc, washed four times with satd. Aq. saturated and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Preparative reverse phase HPLC provided the title compound (54%) as a foam. LCMS m / z (APCI) = 281.1 (M + H).

Example 1 (c)

X Xnx ^ 0h NaSMe X X ^ OH

Br N ^ N -. MeS ^ N ^ N

o ^ Ph MW1 NMP, 180 ° C o ^ Ph

Me me

(S) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-one

ol. A thick-walled microwave flask equipped with a stir bar was charged with (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol (1, 0 equiv), sodium thiomethoxide (4.5 equiv), and N-methylpyrrolidone (10 volume equivalents). The flask was fitted with a septum and cap and heated at 180 ° C in a microwave for 30 min. The reaction mixture was then diluted with 100 volume equivalents EtOAc and washed with 4 χ 100 equivalents water volume and 1 χ 100 equivalents. brine volume The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo Reverse phase preparative HPLC (20% - 80% MeCN / H2 O) provided the title compound (24%) as a white solid. LCMS m / z (APCI) = 287.1 (M + H).

Example 1 (d) AiXNvoh ^ B (OH) 2

N ^ N

Me

N

VNX

ι N

Br

Ph DPPFPdCl2, aq. K2CO3

The

Dioxario, 90 ° C

N

Me

Ph

{S, Z) -1- (1-Phenethyl) -6- (prop-1-enyl) -1H-imidazo [4,5-

b] pyrazin-2-hi. A scintillation vial equipped with a stir bar was charged with (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol (1.0 equiv), (2) -prop-1-enyl boronic acid (2.0 equiv) and (DPPF) PdCl2 (0.10 equiv). The flask was fitted with a septum-coated cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2 N K 2 CO 3 (4.2 volume equivalents) by syringe. The resulting mixture was heated at 90 ° C overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed twice with sat. Aq. saturated and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 5% - 40% EtOAc / Hexanes) provided the title compound (63%) as a not all white foam. LCMS m / z (APCI) -281.1 (M + H).

Scintillation flask equipped with a stir bar was charged with (S) -6-bromo-1- (1-phenylethyl) -1H-Imidazo [4,5-b] pyrazin-2-ol (1.0 equiv) , vinyl boronic acid (2.2 equiv), and (DPPF) PdCl2 (0.10 equiv). The flask was fitted with a septum-coated cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2 N K 2 CO 3 (4.2 volume equivalents) with syringe. The resulting mixture was heated at 90 ° C overnight. The mixture was cooled to

Example 1 (e)

Br

(S) -1- (1-Phenylethyl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2-ol. A room temperature, diluted with 12 volume equivalents EtOAc, washed twice with sat. Aq. saturated, and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Flash vapor chromatography (Biotage MPLC 5% - 40% EtOAc / Hexanes) provided the title compound as a not all white solid (54%). LCMS m / z (APCI) = 267.0 (M + H). Example l (f)

rTNVNx ^ n ^ t-ν

Λ NaH, MeOH, MW X X 4 OH

Br ^ NT N -: -: -_ MeO ^ N ^ N

/ -ph NMP, 200 0C> - ph

Me me

(S) -6-Methoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol.

A thick-walled microwave flask equipped with a stir bar was charged with MeOH (2.0 equiv) and NMP (20 volume equivalents). The resulting solution was added NaH (2.0 equiv), resulting in gas evolution. (S) -6-Bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol (1.0 equiv) was then added to the reaction and the resulting mixture was immediately equipped with a septum and lid and heated to 200 ° C in a microwave for 30 min. The reaction was then diluted with EtOAc, washed twice with sat. Aq. saturated and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Preparative reverse phase HPLC provided the title compound (29%) as a white solid. LCMS m / z (APCI) = 271.1 (M + H). Example 1 (g)

InXnMh Hg (1 atm). Pd / C EtlNXN 4 ° H

o ^ Ph MeOH, 23 0C Λ-Ph

Me me

(S) -1- (1-phenylethyl) -6-ethyl-1H-imidazo [4,5-b] pyrazin-2-ol. a

Scintillation flask equipped with a stir bar was charged with (S) -6-vinyl-1- (1-phenylethyl) -1H-Imidazo [4,5-b] pyrazin-2-ol (1.0 equiv), methanol (280 volume equivalents), and catalytic Pd / C. The resulting mixture was purged with hydrogen for 45 minutes; The reaction was complete as judged by LCMS. The mixture was then filtered through a diatomaceous earth pad and the diatomaceous earth pad was washed twice with MeOH. The solution was concentrated in vacuo. Flash chromatography (Biotage MPLC 5% - 40% EtOAc / Hexanes) provided the title compound (86%) as a foam. LCMS m / z (APCI) = 269.1 (M + H).

Example 2

Synthesis of 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol

N NH2

βΛΝ ^ Βγ

NH2 N2 NH4,

Et ^ Et

XX

Br N NH

MW 150C

Et "Et

2

Step 1: 6-Bromo-N- (pentan-3-yl) pyrazine-2,3-diamine. THE

The title compound was prepared in a manner analogous to Example 1.

Step 1 except 3-Aminopentane (2.6 volume equivalents) was replaced

by (S) -sec-phenethylamine. LCMS m / z (APCI) = 259.0, 260.0 (M + H).

-Ni ^ NH2 ^ nW-N

ζ CDI excess J1 J1 Br N NH - Br N N

THF, 67 ° C / ~ Et

Et Et Et

Step 2: 6-Bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol. The title compound was prepared by treating 6-bromo-N2- (pentan-3-yl) pyrazine-2,3-diamine in a manner analogous to Example 1. Step 2 LCMS m / z (APCI) = 285.0, 287.0 (M + H).

Example 2 (a)

/ -Et Et3N, MW / ~ Et

Et NMP, 120 ° C Et

(E) -1- (pentan-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol. A thick-walled microwave flask equipped with a stir bar was loaded with 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (1.0 equiv) and (F3PAPd (0.15 equiv). The flask was covered by a Parafilm slide and purged with nitrogen for 5-10 min, and N-methylpyrrolidone (11.7 volume equivalents), triethyl amine (2.0 equiv), and (E) -tributyl (prop-1-enyl) stannane (2.0 equiv) were added by syringe. The resulting mixture was immediately fitted with a septum and lid and heated to 120 ° C in a microwave for 20 min. The reaction layer was then diluted with EtOAc, washed three times with water and once with brine.The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.Preparative preparative HPLC provided the title compound (15%) as a LCMS m / z (APCI) = 247.1 (M + H).

Example 2 (b)

Br

I Voh

N

NaSMe

Month

N

Xnvoh

N N

Et

Et MW, NMP, 180 ° C

Et

Et

6- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol.

The title compound was prepared by reacting 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (1.0 equiv), sodium thiomethoxide (1 , 4 equiv), and N-methylpyrrolidone (5.9 volume equivalents) in a manner analogous to Example 1 (c). LCMS m / z (APCI) = 253.0 (M + H). Example 2 (c)

Br '.N.

s

N '

N

N

Voh

Me

B (OH) 2

/> - OH

Et

Et

aq. K2CO3 Dioxane, 90 ° C

(Z) -1- (pentan-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol. The title compound was prepared by reacting 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (1.0 equiv), acid (Z) - prop-1-enyl boronic (1.5 equiv) and (DPPF) PdCl 2 (0.15 equiv) in a manner analogous to Example 1 (d). LCMS m / z (APCI) = 247.0 (M + H).

Example 3

Synthesis of 1- (pentan-3-yl) -1H-imidazo [4,5-b] quinoxalin-2-ol

N NH2

rAci

NH2

Et ^ Et

N NH2 N NH

MW, 120 ° C

Et

Et

2

Step 1: N - (pentan-3-yl) quinoxaline-2,3-diamine. a

Thick-walled microwave flask equipped with a stir bar was loaded with 3-chloroquinoxalin-2-amine (1.0 equiv) and 20 volume equivalents of 3-aminopentane. The flask was fitted with a septum and cap and heated at 120 ° C in a microwave for 30 min. The resulting solution was concentrated in vacuo. Flash chromatography (20% - 60% EtOAc / Hexanes) provided the title compound (78%) as a yellow solid. LCMS m / z (APCI) = 231.1 (M + H).

Excess CDI

THF, 67 ° C

Step 2: 1- (pentan-3-yl) -1H-imidazo [4,5-b] quinoxin-2-ol.

The title compound was prepared by treating N2- (pentan-3-yl) quinoxaline-2,3-diamine in a manner analogous to Example 1. Step 2 LCMS m / z (APCI) = 257.2 (M + H) .

Example 3 (a)

KMeBF3

Br '

.N, Nf

N

\ AH. Cs2CO3

N Hinvann QD ° C.

Et

Me'

N

N

N

Voh

N

Et

Et

Et

Synthesis of (Z) -1- (pentan-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol. A scintillation vial equipped with a stir bar was loaded with 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (1.0 equiv), KF3BMe (2.0 equiv), Cs2CO3 (3.0 equiv) and (DPPF) PdCb (0.20 equiv). The flask was fitted with a septum-coated cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (25 volume equivalents) and degassed water (5 volume equivalents) with syringe. The resulting mixture was heated at 90 ° C overnight. The mixture was cooled to room temperature, diluted with 15 mL EtOAc, washed twice with sat. Aq. saturated and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 5% - 40% EtOAc / Hexanes) provided the title compound (53%) as a white solid. LCMS m / z (APCI) = 221.1 (M + H).

Example 4

Synthesis of 6-Ethinyl-1- (pentan-3-yl) -1H-imidazo [4,5-

b] pyrazin-2-ol

Example 4 (a)

1- (pentan-3-yl) -6 - ((trimethylsilyl) ethynyl) -1H-imidazo [4,5-

b] pyrazin-2-ol.

A mixture of 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (3.75 g, 13.2 mmol)), trimethylsilylacetylene (2.8 mL, 19.8 mmol), PdCl 2 (PF) 2 (0.93g, 1.32 mmol), CuI (0.5 g, 2.64 mmol) and triethylamine (5.5 mL, 39.5 mmol) in DMF (50 mL) was purged with N 2 for 30 seconds, followed by stirring at 80 ° C. After 3 hours the reaction mixture was diluted with EtOAc, washed with NH 4 Cl solution, dried over Na 2 SO 4, and concentrated in vacuo. Silica gel purification (Biotage MPLC 10 - 80% EtOAc / hexanes) provided the title compound (3.2 g, 80%) as a brown solid. Example 4 (b)

6-Ethinyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-yl. An

1- (pentan-3-yl) -6 - ((trimethylsilyl) ethynyl) -1H-imidazo [4,5-b] pyrazin-2-ol (3.2 g, 10.6 mmol) mixture, KF ( 1.6 g, 27.5 mmol) in MeOH / THF / H2 O (50 mL, 2/2/1) was stirred at room temperature. Upon complete conversion by LCMS, the solution was concentrated in vacuo, diluted with EtOAc, washed with NH 4 Cl solution, dried over Na 2 SO 4, and concentrated in vacuo. Silica gel purification (Biotage MPLC 10 - 80% EtOAc / Hexanes) provided a brown solid, which was washed with 15% EtOAc / hexanes to afford the title compound product as a white solid (0.9 g, 37% ).

Example 5

Synthesis of 6- (dimethylamino) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol

Example 5 (a)

tert-butyl 5-bromo-2-oxo-3- (pentan-3-yl) -2,3-

dihydroimidazo [4,5-b] pyrazine-1-carboxylate. In a solution of 6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (5.0 g, 17.6 mmol) in DCM (80 mL) containing triethylamine (7.34 mL, 52.8 mmol) was added BOC 2 O (7.0 g, 35 mmol). The reaction mixture was stirred at room temperature overnight, washed with NaHCO 3 solution, dried over Na 2 SO 4 and concentrated in vacuo. Purification on silica gel (Biotage MPLC 10 - 50% EtOAc / Hexanes) provided the desired product as a white solid (1.7 g, 25%).

Example 5 (b)

Mouth

\\ T y = 0 M Pd3 (Clba) 2, NaOtBu HCI

sK ^ n + / ^ -

_ / BiPhP (Cy) 2, Toluene1 120 0C

6- (dimethylamino) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol. A mixture of tert-butyl 5-bromo-2-oxo-3- (pentan-3-yl) -2,3-dihydroimidazo [4,5-b] pyrazine-1-carboxylate (200 mg, 0.52 mmol) , dimethylamine (0.5 mL, 2M in THF, 1.0 mmol), Pd3 (dba) 2 (48 mg, 0.052 mmol), BiFP (Cy) 2 (37 mg, 0.10 mmol) and NaOtBu (150 mg 1.56 mmol) in anhydrous toluene (4 mL) was purged with N 2 for 15 seconds and then stirred at 120 ° C for 20 minutes in microwave. The mixture was diluted with EtOAc, washed with NaHCO 3 solution, dried over Na 2 SO 4 and then concentrated in vacuo to afford a dark muddy residue. The residue was dissolved in MeOH (10 mL) and treated with 1 mL 4M HCl in dioxane. After one hour, the reaction was concentrated, diluted with EtOAc, washed with NaHCO 3, dried over Na 2 SO 4 and concentrated in vacuo. Silica gel purification (Biotage MPLC 10 - 70% EtOAc / hexanes) provided the title compound as a light yellow solid (42 mg, 32%).

Example 6

Preparation of Sarcomeric Muscle Proteins

Skeletal

Actin was purified by first preparing an ether powder of

cardiac muscle (Zot HG and Potter J D. (1981) Preparative Biochemistry 11: 381-395) as described below. Subsequently, actin was cycled between filamentous and soluble state through centrifugation and dialysis cycles (Spudich JAe Watt S. (1971) J. Biol. Chem. 246: 4866-4871). It was stored in filamentous state at 40 ° C.

Tropomyosin was extracted from ether powder and separated from other proteins based on pH-dependent precipitations, followed by successive fractions of 53% and 65% ammonium sulfate (Smillie LB. (1981) Methods Enzymol 85 Pt B: 234-41 ). Troponins were isolated as an intact complex of TnC, TnT, and TnI. Ether powder is extracted into a high salt buffer. Successive 30% and 45% ammonium sulfate fractions were made; The precipitate was solubilized by dialysis in a low salt buffer and then further purified on a Toyopeart DEAE column with a 25 - 350 mM KCl gradient. There was no measurable ATPase in any of the components except for myosin, which naturally had a very low basal ATPase in the absence of actin.

Just prior to selection, actin, tropomyosin and troponin complex are mixed together in the desired ratio (eg 7: 1: 1) to achieve maximum calcium regulation of the actin filament. Selection is conducted at a pCa = 6.5. This calcium concentration is in the physiological range during muscle contraction.

To measure ADP generation during the reaction, a pyruvate kinase / lactate dehydrogenase / NADH (PK / LDH) coupled enzyme system is added to the actin. Myosin is maintained separately. The plates are read in real time so that kinetic curves are obtained. These compounds are in DMSO and have already been located in the bottom of 384 well plates at 10 to 40 μg / ml final concentration.

Example 7

Actin Preparation

1. Extract powder (as prepared in Example 6 or 7 below) with 20 ml buffer A (see below, add BME and ATP just before use in each of the following steps) per gram of powder (200 ml per 10 g ). Use a large 4 1 beaker for 150 g of powder. Mix vigorously to dissolve the powder. Stir at 40 ° C for 30 min.

2. Separate the extract from the hydrated powder by squeezing through several layers of coarse cotton gauze. The gauze should be pre-sterilized by microwave damping for 1 - 2 min.

3. Extract the residue with the same volume of buffer A and combine the extracts.

4. Spin on JLA10 rotor (s) for 1 h at IOK rpm (40 ° C). Collect the supernatant through 2 layers of cotton gauze.

5. Add 0.2 mM ATP and 50 mM MgCl2. Shake on stirred plate at 40 ° C for 60 minutes to allow actin to polymerize / form para-crystals.

Slowly add 0.6 M solid KCl (45 g / l). Stir at 40 ° C for 30 min.

7. Rotate JLA1 rotor (s) at 0 to 10 K rpm for 1 h.

8. Depolymerization: Quickly rinse the surface of the pellets with buffer A and discard the wash. Soften the pellets by preincubating on ice with small amount of Buffer A in each tube (use less than half of the total final resuspension volume in all tubes). Manually resuspend first with cell scraper and combine pellets. Wash the tubes with extra buffer using a 25 ml pipette and motorized pipettor, aggressively removing actin from the sides of the tubes. Homogenize in large dounce in cold buffer on ice. Use 3 ml per gram of originally extracted powder.

9. Dialysate in contact with buffer A with 4 changes over a period of 48 hours.

10. Collect dialyzed actin and spin on 45Ti rotor at 40 K rpm for 1.5 h (40 ° C).

11. Collect supernatant (G-Actin). Save a sample for gel analysis and protein concentration determination.

Polymerize G-actin for storage, add 50 mM KCl (3 M stock), 1 mM MgCl 2 and 0.02% NaN 3 (10% stock). Store at 40 ° C. Do not freeze.

Buffer A: 2 mM Tris / HCl, 0.2 mM CaCl2, 0.5 mM (36 μΐ / ΐ) 2-mercaptoethanol, 0.2 mM Na2 ATP (fresh add) and 0.005% Na-azide; pH 8.0.

Example 8 Powder Preparation

1. The volumes are supplied by about 1000 g of muscle.

chopped.

2. Pre-cut and boil cotton gauze for 10 min in water.

Drain and dry.

3. Mince chicken breast in a pre-cooked meat grinder

Chilled

4. Extract with stirring in 2 l of 0.1 M 0.5 M KCl phosphate-K, pH 6.5 for 10 min at 40 ° C. Spin 5000 rpm, 10 min, 40 ° C in JLA. Collect the pellet.

5. Extract the pellets with stirring with 2 l of 0.05 M NaHCO3 for 5 min. Spin 5000 rpm, 10 min, 40 ° C in JLA. Collect the pellet. Repeat the extraction one more time.

6. Extract the filtered residue with 2 l of 1 mM EDTA, pH 7.0 for 10 min with stirring.

7. Extract with 2 L of H2O for 5 min with stirring. Rotate 10,000 rpm, 15 min, 40 ° C in JLA. Carefully collect the pellet, part of which will be loose and gelatinous.

8. Extract 5 times with acetone (2 L of acetone for 10 min each with stirring). Squeeze through cotton gauze gently. All acetone extractions are performed at room temperature. Acetone should be pre-cooled to 40 ° C.

9. Drying: Place the strained filtered residue on a cotton gauze in a large glass tray and leave in a hood overnight. When the residue is dry, place in a wide mouth plastic bottle and store at 20 ° C. Example 9

Toggle Powder Preparation

Based on Zot & Potter (1981) Prep. Biochem. 11 (4) pp.

381-3985

1. Dry out the left ventricles of the heart muscle. Remove as much of the pericardiac tissue and fat as possible. Grind in a pre-cooled meat grinder. To weight.

2. Prepare 5 volumes of Extract buffer (see below). Make sure the pH = 8.0. Then homogenize the meat in a combiner 4 times 15 sec in mix with 15 sec interval. Do this with 1 volume weight / volume of buffer taken from the 5 volumes already prepared. Add the homogenate back to the extract buffer and shake until thoroughly mixed (5 minutes).

3. Filter through a layer of cotton gauze into large polypropliene colander. Resuspend again in 5 volumes of extract buffer as above.

4. Repeat Step 3 four more times. At the end, do not resuspend in extraction buffer, but proceed to Step 5. The pellets should be yellowish white.

5. Resuspend in 3 volumes (according to original weight) of cold 95% ethanol. Shake for 5 min and squeeze through cloth gauze as above, repeat twice more.

6. Weigh the squeezed residue and then resuspend in 3 volumes (fresh feet / volume) of cold diethyl ether.

Repeat step 6 a total of three times.

8. Leave overnight in a single layer over a cotton gauze in a glass tray. 9. When dry, collect dust, weigh and store in a wide-mouth jar at 40 ° C.

EXTRACT BUFFER: 50 mM KCl, 5 mM Tris pH 8.0 Prepare as 50-fold concentrate: For 2 1.

250 mM Tris pH 8.0. Tris Base (121.14 g / mol, 60.6 g) pH 8.0 with conc. HCl, then add: 2.5 M KCl (74.55 g / mol, 372 g) Example 10

Purification of Skeletal Muscle Myosin

See, Margossian, S.S. and Lowey, S. (1982) Methods Enzymol. 85, 55-123 and Goldmann, W.H. and Geeves, M.A. (1991) Anal. Biochem. 192, 55-58,

Solution A: 0.3 M KCl, 0.15 M Potassium Phosphate, 0.02 M EDTA, 0.005 M MgCl2, 0.001 M ATP, pH 6.5.

Solution Β: 1 M KCl, 0.025 M EDTA, 0.06 M Potassium Phosphate, pH 6.5,

Solution C: 0.6 M KCl, 0.025 M Potassium Phosphate, pH 6.5, Solution D: 0.6 M KCl, 0.05 M Potassium Phosphate, pH 6.5, Solution E: 0.15 M Phosphate Potassium phosphate, 0.01 M EDTA, pH 7.5, Solution F: 0.04 M KCl, 0.01 M Potassium phosphate, 0.001 M

DTT, pH 6.5,

Solution G: 3 M KCl, 0.01 M potassium phosphate, pH 6.5. All procedures are performed at 40 ° C.

1, Obtain -1000 g of skeletal muscle such as rabbit skeletal muscle.

2. Grind twice; extract with 2 l of solution A for 15 min while stirring; add 4 l of cold H2O, filter through gauze; Dilute with cold H2O to the ionic strength of 0.04 (about 10-fold); leave to settle for 3 h; collect the precipitate at 7000 rpm in GSA rotor for 15 min.

3. Disperse the pellet in 220 ml of solution B; dialysate overnight with 6 l of solution c; slowly add -400 ml of equal volume of cold distilled H2O; stir for 30 min; centrifuge at 10,000 rpm per min in GSA rotor.

4. Centrifuge the supernatant at 19,000 rpm for 1 h.

5. Dilute the supernatant to the ionic strength of 0.04 (~ 8 times); letting myosin settle overnight; Collect about 5-6 1 of fluffy myosin precipitate by centrifugation at 10,000 rpm for 10 min in GSA rotor.

6. Resuspend pellets in minimum volume of solution g; dialysate overnight with 2 1 solution D; centrifuge at 19,000 rpm for 2 hours in cellulose nitrate tubes; pierce the tubes and separate the myosin from fat and insoluble pellet.

7. Dilute the supernatant to 5 - 10 mg / ml and dialysate with solution E extensively, column load DEAE-sephadex.

8. Pre-equilibrate with solution E; apply 500 - 600 g of micaine to 30 ml; wash with 350 ml of solution E; elute with linear gradient of 0 - 0.5 M KCl in solution E (2 χ 1 liter); collect 10 ml fractions; pooling myosin fractions (> 0.1 M KCl); concentrate overnight dialysis with solution F; centrifuge at 25000 rpm for 30 min; Store as above.

9. The myosin is then cut with chymotrypsin or papain in the presence of EDTA to generate the SI fragment, which is soluble under low salt conditions optimal for ATPase activity (Margossian above).

Example 11

Using procedures similar to those described herein, the compounds of the following table were synthesized and tested. Name m / z Ion SKM MF AC 1.4 (μΜ) (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol 319.0 [M + H] +; [M + H] + 0.45 (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 319.0; 321.0 [M + H] +; [M + H] + 0.45 (R) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol 319.0; 321.0 [M + H] +; [M + H] + 2.4 (R) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 319.0; 321.0 [M + H] +; [M + H] + 2,41-benzyl-6-bromo-1H-imidazo [4,5-b] pyrazin-2-ol 305.1; 307.1 [M + H] +; [M + H] + 23.5 1-benzyl-6-bromo-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 305.1; 307.1 [M + H] +; [M + H] + 23.5 (S) -6- (methylthio) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-ol 287.1 [M + H ] + 1,1 (S) -6- (methylthio) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one 287.1 [M + H ] + 1,1 1-benzyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol 273.0 [M + H] + 22,61-benzyl-6- (methylthio ) -1 H -imidazo [4,5-b] pyradin-2 (3H) -one 273.0 [M + H] + 22.6 (R) -6- (methylthio) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-ol 287.0 [M + H] + 2.9 (R) -6- (methylthio) -1- (1-phenylethyl) -1 H- imidazo [4,5-b] pyrazin-2 (3H) -one 287.0 [M + H] + 2.9 (S) -6- (2-methylprop-1-enyl) -1- (1-phenylethyl ) -1H-imidazo [4,5-b] pyrazin-2-ol 295.1 [M + H] + 2.7 (S) -6- (2-methylprop-1-enyl) -1 - (1 - phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 295.1 [M + H] + 2.7 (S) -6-cyclohexenyl-1- (1-phenylethyl) -1 H-imidazo-4,5-b] pyrazin-2-ol 321.1 [M + H] + 31.0 (S) -6-cyclohexenyl-1- (1-phenylethyl) -1H-imidazo [4, 5-b] pyrazin-2- (3 H) -one 321.1 [M + H] + 31.0 (S5Z) -1 - (1-phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol 281.1 [M + H] + 1.0 (S5Z) -1- (1-phenylethyl) -6- (pr op-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one 281.1 [M + H] + 1.0 (S) -1- (1-phenylethyl) - 6-vinyl-1 H -imidazo [4,5-b] pyrazin-2-ol 267.0 [M + H] + 2.4 (S) -1- (1-phenylethyl) -6-vinyl-1 H -imidazo [4,5-b] pyrazin-2 (3H) -one 267.0 [M + H] + 2.4 (S) -6-ethyl-1- (1-phenylethyl) -1H-imidazo [ 4,5-b] pyrazin-2-ol 269.1 [M + H] + 17.4 (S) -6-ethyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2- (3H) -one 269.1 [M + H] + 17.4 (S) -1- (1-phenylethyl) -6-propyl-1 H -imidazo [4,5-b] pyrazin-1-one 2-ol 283, [M + H] + 29.7 (S) -1- (1-phenylethyl) -6-propyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 283 , 1 [M + H] + 29.7 (6) -6-methoxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-ol 271.1 [M + H ] + 8.8 (6) -6-methoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 271.1 [M + H] + 8 4,8-bromo-1-cycloexyl-1H-imidazo [4,5-b] pyrazin-2-ol 296.9; 298.9 [M + H] +; [M + H] + 10.4 6-bromo-1-cyclohexyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 296.9; 298.9 [M + H] +; [M + H] + 10.4 1-cyclohexyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol 265.1 [M + H] + 13.9-cycloexyl- 6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3h) -one 265.1 [M + H] + 13.9 (Z) -1-cycloexyl-6- (propyl) 1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol 259.1 [M + H] + 6.0 (Z) -1-cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one 259.1 [M + H] + 6.0 (E) -1-cycloexyl-6- (prop-1-enyl) - 1H-imidazo [4,5-b] pyrazin-2-ol 259.1 [M + H] + 6.1 (E) -1-cycloexyl-6- (prop-1-enyl) -1H-imidazo [ 4,5-b] pyrazin-2 (3H) -one 259.1 [M + H] + 6.1 (S5E) -1- (1-phenylethyl) -6- (prop-1-phenyl) -1 H-imidazo [4,5-b] pyrazin-2-ol 281.1 [M + H] + 1.6 (S3E) -1- (1-phenylethyl) -6- (prop-1-enyl) -1 H-imidazo [4,5-b] pyrazin-2 (3H) -one 281.1 [M + H] + 1,66-bromo-1-isopropyl-1H-imidazo [4,5-b] pyrazin-1 2-ol 259.0 [M + H] + 6.0 6-bromo-1-isopropyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 259.0 [M + H] + 6.0 1-isopropyl-6- (methylthio) -1-imidazo [4,5-b] pyrazin-2-ol 225.1 [M + H] + 6.71-isopropyl-6- (methylthio) -1-imidazo [4,5-b] pyrazin-2 (3H) -one 225.1 [M + H] + 6.7 (Z) -1-isop ropyl-6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol 219.2 [M + H] + 4.6 (Z) -1-isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one 219.2 [M + H] + 4,6 (S) -6-ethoxy-1 - ( 1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol 285.2 [M + H] + 10.6 (S) -6-ethoxy-1- (1-phenylethyl) -1 H-imidazo [4,5-b] pyrazin-2 (3H) -one 285.2 [M + H] + 10.6 6-bromo-ethoxy-1- (penta-3-yl) -1H-imidazo [ 4,5-b] pyrazin-2-ol 286.0; 288.0 [M + 2H] 2+; [M + 2H] 2+ 0.25 O- (methylthio) -1- (penta-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 253.1 [M + H] + 0.4 6- (methylthio) -1- (penta-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 253.1 [M + H] + 0, 4 (E) -1- (penta-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol 247.1 [M + H] + 0 (E) -1- (penta-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 247.1 [M + H] + 0.4 (E) -1- (penta-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2-ol 247.1 [M + H] + 0.6 (E) -1 - (penta-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 247.1 [M + H] + 0.6 6-methyl-1- (penta-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 221.1 [M + H] + 0.53 6-methyl-1- (penta-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 221.1 [M + H] + 0.53 (S, Z) -6- (hex-2-enyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol 3,1 2-hydroxy-1- (penta-3 -1yl) -1H-imidazo [4,5-b] pyrazino-232,1 [M + H] + 36,4-6-carboitrile 2-oxo-3- (pentan-3-yl) -2,3- dihydro-1H-imidazo [4,5-b] pyrazine-5-carbonitrile 232.1 [M + H] + 36.4 (R) -6-bromo-1-sec-butyl-1H-imidazo [4, 5-b] pyrazin-2-ol 273.0 [M + H ] + 1.5 (R) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 273.0 [M + H] + 1.5 (S) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2-ol 272.0 [M + H] + 0.8 (S) -6-bromo-1 -sec-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 271.0 [M + 2H] 2+; 0.8 6-bromo-1-tert-butyl-1H-imidazo [4,5-b] pyrazin-2-ol 271.0 [M + 2H] 2+; 0.8 6-bromo-1-tert-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one 272.0 [M + 2H] 2+; 0.8 2- (6-Bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) butanoic acid 299.0 [MH] -> 49 2- (6-Bromo-2 acid -oxo-2,3-dihydro-1H-imidazo [4,5-b] pyrazin-1-yl) butanoic 299.0 [MH] -> 49 2- (6-bromo-2-hydroxy-1 H -imidazo [4,5-b] pyrazin-1-yl) -1-morpholinobutan-1-one 370.0 [M + H] +> 49 6-bromo-1- (1-morpholine-1-oxobutan-2-yl ) -1H-imidazo [4,5-b] pyrazin-2- (3H) -one 370.0 [M + H] +> 49 (R) -6-bromo-1- (1-hydroxybutan-2-yl ) -1H-imidazo [4,5-b] pyrazin-2-ol 285.0 [MH] -1,1 (R) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 285.0 [MH] -1,1 (S) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4 , 5-b] pyrazin-1-ol 285.0 [MH] - 19.1 (R) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 285.0 [MH] - 19,16-bromo-1- (1-methoxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 301.0 [M + H] + 4.9 6-bromo-1- (1-methoxybutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one 301, 0 [M + H] + 4.9 1 - (1-aminobutan-2-yl) -6-bromo-1 H -imidazo [4,5-b] pyrazin-2-ol 287.0 [M + 2H] i +; 1,1 1- (1-aminobutan-2-yl) -6-bromo-1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one 287.0 [M + 2H] 2+; 1,1 6-bromo-1- (1- (methylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 30.00 [M + H] + 45, 7 6-bromo-1- (1- (methylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 300.0 [M + H] + 45.7 6-bromo-1- (1- (methylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 315.0 [M + 2H] 2+; 43,8 6-bromo-1 - (1- (methylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 315.0 [M + 2H] 2+ ; 43.8 6-bromo-1- (1- (4-methylpiperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 369.0 [M + H ] + 14.9 6-bromo-1- (1- (4-methylpiperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 369, [M + H] + 14.9 (R) -6-bromo-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 356.0; 358.0 [M + H] + [M + H] + 0.3 (R) -6-bromo-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-1-one 2 (3H) -one 356.0; 358.0 [M + H] +; [M + H] + 0.3 (S) -6-bromo 1- (1-morpholinobutan-2-yl) -1H-356.0; [M + H] +; > 49 imidazo [4,5-b] pyrazin-2-ol 358.0 [M + H] + (S) -6-bromo 1- (1 -morflinobutan-2-yl) -1H-imidazo [4,5 -b] pyrazin-2 (3H) -one 356.0; 356.0 [M + H] +; [M + H] +> 49 (E) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol 219.1 [M + H] + 7.1 (E) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one 219.1 [M + H] + 7.1 1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 207.1 [M + H] + 16.0 * 1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 207.1 [M + H] + 16.0 * methyl 4- (2,6-bromo-2-hydroxy-1H-imidazo [ 4,5-b] pyrazin-1-yl) butyl) piperazine-1-carboxylate 414.0 [M + 2H] 2+; 0.9 * methyl 4- (2- (6-bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyrazin-1-yl) butyl) piperazine-1-carboxylate 414, 0 [M + 2H] 2+; 0.9 * 6-bromo-1- (1- (3-methylsulfonyl) piperazin-1-yl-butan-2-yl) -1H-imidazol [4,5-b] pyrazin-2-ol 434.0 [ Μ + 2ΗΓ; [3,2 * 6-bromo-1- (1- (3-methylsulfonyl) piperazin-1-yl-butan-2-yl) -1H-imidazol [4,5-b] pyrazin-2 (3H) -one 434.0 [M + 2H] 2+ 3.2 * 5-bromo-1- (pentan-3-yl) -1H-imidazo (4,5-b] pyrazin-2-ol 285.0; 287.0 [M + H] +; [M + H] + 11.5 5-bromo-1- (penta-3-yl) -1 H -imidazo [4,5-b] pyrazin-2- (3H) -one 285.0, 287.0 [M + H] +; [M + H] + 11.5 1- (penta-3-yl) -1H-imidazo [4,5-b] quinoxalin-2-ol 257, 1 [M + H] + 19.8 1- (penta-3-yl) -1H-imidazo [4,5-b] quinoxalin-2 (3H) -one 257.1 [M + H] + 19.8 6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 231.2 [M + H] + 0.1 ** 6-ethynyl-1 - ( pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one 231.2 [M + H] + 0.1 ** 1 - (penta-3-yl) - 6- (trifluromethyl) -1H-imidazo [4,5-b] pyrazin-2-ol 275.2 [M + H] + 10,4 ** 1- (penta-3-yl) -6- (trifluromethyl ) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 275.2 [M + H] + 10.4 ** 6-bromo-1- (2-methyl-1-morpholinopropan-2 -yl) -1H-imidazo [4,5-b] pyrazin-2-ol 356.0; 358.0 [M + H] +; [M + H] + 16.4 ** 6-bromo-1 - (2-methyl-1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H-one 356.0; 358.0 [M + H] +; [M + H] + 16.4 ** 6-bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 342.0; 344.0 [M + H] +; [M + H] +> 49 6-bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 342.0; 344.0 [M + H] +; [M + H] +> 49 6-methoxy-1-penta-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 237.1 [M + H] + 2.2 * * 6-methoxy-1-penta-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 237.1 [M + H] + 2.2 ** (R) -6-bromo-1- (1-morpholinopropoprop-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol 342.0; 344.0 [M + H] +; [M + H] + 5.2 ** (R) -6-bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 342 .0; 344.0 [M + H] +; [M + H] + 5.2 ** 1- (penta-3-yl) -1H-imidazo [4,5-b] pyrazine-2,6-diol 232.2 [M + H] +> 496 -hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2- (3H) -one 223.2 [M + H] +> 49 1 - (penta-3- yl) -6- [prop-2-ynyl) -1H-imidazo [4,5-b] pyrazin-2-ol 245.2 [M + H] +> 49 1 - (penta-3-yl) - 6-prop-1-ynyl) -1H-imidazo [4,5-245,2 [M + H] +> 49 b] pyrazin-2- (3H) -one 1- (1-morpholinobutan-2-yl ) -1 H -imidazo [4,5-b] pyrazin-2-yl 278.0 [M + H] +> 49 1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5- b] pyrazin-2 (3H) -one 278.0> 49 1- (ethylpropyl) -6- (1-methylpyrazol-4-yl) imidazo [4,5-b] pyrazin-2-yl 287.1 [M + H] + 15 6-bromo-1- (propylbutyl) imidazo [4,5-b] pyrazin-2-ol 313.1 [M + H] + 0.7 1 - [(1 R) -3-methyl -1- (morpholin-4-ylmethyl) butyl] -6-bromoimidazo [4,5-b] pyrazin-2-ol 384 [M + H], 0.5 1- (ethylpropyl) -6-vinylimidazo [4, 5-b] pyrazin-2-ol 233.1 [M + Hf 2,31- (ethylpropyl) -6- (1-methylvinyl) imidazo [4,5-b] pyrazin-2-ol 247 [M + H ] + 0.6 1- (ethylpropyl) -6- (methylethyl) imidazo [4,5-b] pyradin-2-ol 249 [M + H] + 29,6 6-chloro-1- (ethylpropyl) imidazo [ 4,5-b] pyrazin-2-o 1,239.1 [M + H] + 0.7 6- (dimethylamino) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol 250.1 [M + H] + 2.2 1 - ((1R) -1-methyl-2-morpholin-4-ylethyl) -6-bromoimidazo [4,5-b] pyrazin-2-ol 342,344 (M + H), (M + 2 + H) 5.19 1- (ethylpropyl) -6-ethylnylimidazo [4,5-b] pyrazin-2-ol 229 (MH) 0.15 1- (ethylpropyl) -6-methoxyimidazo [4,5-b] pyrazin-2 -oI 237 (MH) 2.20 1- (1,1-dimethyl-2-morpholin-4-ylethyl) -6-bromoimidazo [4,5-b] pyrazin-2-ol 356, 358 (M + 1) (M + 2 + H) 19.11 6- (1H-1,2,3-triazol-4-yl-1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol 274 (M + H) + 46.64 1- (ethylpropyl) -6- (trifluoromethyl) imidazo [4,5-b] pyrazin-2-ol 275 (M + H) 10.37 1 - {(1R) -1 - (morpholin -4-ylmethyl) propyl] -6-ethynylimidazo [4,5-b] pyrazin-2-ol 302 (M + H) 0.13 1- (ethylpropyl) -6- {2- [1- (ethylpropyl) - 2-hydroxyimidazo [4,5-e] pyrazin-6-yl] ethynyl} imidazo [4,5-b] pyrazin-2-ol 435 (M + H) 19.32 6- (dimethylamino) -1- (ethylpropyl ) imidazo [4,5-b] pyrazin-2-ol 250 (M + H) 2,79 6-ethyl-1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol 235 [M + H ] 8.58

+ Average Value

í Median value

Using procedures similar to those described

Here, the compounds of the following table were also synthesized and tested.

NAME

(S) -1- (2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-6-yl) ethanone

(S) -6-Acetyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b 1-pyrazin-2 (3H) -one (S) -6-isobutyl-1- (1-phenylethyl) -1 H-imidazo [4,5-b] pyrazin-2-ol (S) -6-isobutyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -6-Hexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol

(S) -6-Hexyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -6-Cyclohexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol

(S) -6-Cyclohexyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -1- (1-phenylethyl) -1H-imidazo [4,5-blpyrazin-2-ol

(S) -1- (1-phenylethyl) -1H-imidazo [4,5-bpyrazazin-2 (3H) -one_ (S) -2-hydroxy-1- (1-phenylethyl) -1H-imidazo acid [4,5-b] pyrazine-6-carboxylic_

(S) -2-Oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxylic acid

(S) -methyl 2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carboxylate

(S) -methyl 2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-earboxylate

(S) -2-Hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carbonitrile

(S) -2-Oxo-3- (1-phenylethyl) -23-dihydro-1H-imidazo [4,5-b] pyrazine-6-carbonitrile

(S) -2-Hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carboxamide

(S) -2-Oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide

(S) -2-Hydroxy-N-methyl-1- (1-phenylethyl) -1 H -imidazo [4,5-bpyrazine-6-carboxamide]

(S) -N-Methyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide

(S) -2-Hydroxy-N.N-dimethyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide

(S) -N, N-Dimethyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide

(S) -N, N-Diethyl-2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carboxamide

(S) -N.N-Diethyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo- [4,5-b] pyrazine-5-one

carboxamide_

(S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (morpholino) methanone

(S) -6- (morpholino-4-carbonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (piperidin-1-yl) methanone

(S) -1- (1-phenylethyl) -6- (piperidino-1-carbonyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one

(S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (4-methylpiperazin-1-yl) methanone

(S) -6- (4-methylpiperazine-1-carbonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -N-Benzyl-2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carboxamide

(S) -N-Benzyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide

(S) -6 - ((dimethylamino) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b3pyrazin-2-ol]

(S) -6 - ((dimethylamino) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -6- (morpholinomethyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol

(S) -6- (morpholinomethyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -1- (1-phenylethyl) -6-piperidin-1-ylmethyl) -1H-imidazo [4,5-b] pyrazin-2-ol

(S) -1- (1-phenylethyl) -6- (piperidin-1-ylmethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -6 - ((4-methylpiperazin-1-yl) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-blpyrazin-2-ol]

(S) -6 - ((4-methylpiperazin-1-yl) methyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -6- (2-hydroxypropan-2-yl) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-ol

(S) -6- (2-hydroxypropan-2-yl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

6- (methylsulfinyl) -1 - ((S) -1-phenylethyl) -! H-imidazo [4,5-b] pyrazin-2-ol

6- (methylsulfinyl) -1 - ((S) -1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(S) -6- (methylsulfonyl) -1- (1-phenylethyl) -! H-imidazo [4,5-b] pyrazin-2-ol

(S) -6- (methylsulfonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one 6-cyclopropyl-1-one

(pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol

6-cyclopropyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

6-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol

6-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

1-cyclopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol

1-cyclopropyl-6- (methylthio) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one

6- (methylthio) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-bpyrazin-2-ol]

6- (methylthio) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(E) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol

(E) -1-Cyclopropyl-6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(E) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol (E) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(Z) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol

(Z) -1-Cyclopropyl-6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

(Z) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol

(Z) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

6-bromo-1-cyclopropyl-1H-imidazo [4,5-b] pyrazin-2-ol

6-bromo-1-cyclopropyl-1H-imidazo [4,5-b] pyrazin-2- (3H) -one

5- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol

5- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

5-ethyl-1- (pentan-3-yl) -1H-imidazot4,5-b] pyrazin-2-ol

5-ethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

1- (pentan-3-yl) -5-vinyl-1H-imidazo [4,5-b] pyrazin-2-ol

1- (pentan-3-yl) -5-vinyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -on a

methyl 2-hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxylate methyl 2-oxo-1- (pentan-3-yl) -2,3-dihydro -1H-imidazo [4,5-b] pyrazine-5-carboxylate

2-hydroxy-N, N-dimethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxamide

N, N-Dimethyl-2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide

2-hydroxy-N-methyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxamide

N-methyl-2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide

1- (2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-5-yl) ethanone

5-acetyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -on a

(S) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] quinoxalin-2-ol

(S) -1- (1-phenylethyl) -1H-imidazo [4,5-b] quinoxalin-2 (3H) -one

2- (6-bromo-2-hydroxy-1 H -imidazo [4,5-b] pyrazin-1-yl) propane-1,3-diol

6-bromo-1- (1,3-dihydroxypropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -on a

6-bromo-1- (2-morpholinoethyl) -1H-imidazo [4,5-b] pyrazin-2-ol

6-bromo-1- (2-morpholinoethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one

While some embodiments have been shown and described, various modifications and substitutions may be made therein, without departing from the spirit and scope of the invention. For example, for purposes of constructing the claims, the claims set forth below are not intended to be interpreted in any way more strictly than their literal language, and thus the exemplary embodiments of the report are not intended to be read within the claims. Therefore, it should be understood that the present invention has been described by way of illustration and not limitation of the scope of the claims.

Claims (23)

1. At least one chemical entity, characterized in that it is chosen from the compounds of formula I and compounds of formula II: <formula> formula see original document page 86 </formula> and their pharmaceutically acceptable salts, wherein R 1 and R 4 are independently selected from hydrogen, halo, hydroxy, optionally substituted acyl, optionally substituted alkyl, optionally substituted amino, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, sulfonyl, sulfanyl, sulfinyl optionally substituted carboxy, alkoxycarbonyl and cyano; and alternatively R 4 and R 1 taken together with any intervening atoms form a fused ring system selected from optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused cycloalkyl, and optionally substituted fused heterocycloalkyl; and R2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; provided that R 1 is not hex-1-enyl; and provided that the compound of Formula I or the compound of Formula II is not (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) - one; one; one; or [1,5,6-trimethyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1-methyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (3-nitrobenzyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) - [5- (hydroxymethyl) -1,6-dimethyl-1H-imidazo [4, 5-b] pyrazin-2 (3H) - [1- (piperidin-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one At least one chemical entity according to claim 2, characterized in that R 2 is selected from optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy and optionally substituted heterocycloalkyl. At least one chemical entity according to claim 2, characterized in that R 2 is selected from heterocycloalkyl, cycloalkyl, lower alkyl and optionally substituted phenyl substituted hydroxy, optionally substituted alkoxy, optionally substituted amino and optionally substituted heterocycloalkyl . At least one chemical entity according to claim 3, characterized in that R2 is selected from I- (R) -phenylethyl, 1- (S) -phenylethyl, benzyl, 3-pentyl, 4-heptyl, 4- methyl-1-morpholinopentan-2-yl isobutyl, cyclohexyl, cyclopropyl, sec-butyl, tert-butyl, isopropyl, 1-hydroxy butan-2-yl, tetrahydro-2H-pyran-4-yl, imethoxybutan-2-one yl, 1-aminobutan-2-yl, and 1-morpholinobutan-2-yl. At least one chemical entity according to any one of claims 1 to 4, characterized in that R 1 is selected from hydrogen, halo, acyl, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, dialkylamino, amino substituted by an alkyl group and by a group selected from acyl, aminocarbonyl, alkoxycarbonyl, and sulfonyl; optionally substituted lower alkoxy; and -3- (optionally substituted lower alkyl). At least one chemical entity according to claim 5, characterized in that R 1 is selected from hydrogen, halo, acyl, alkenyl, alchemy, lower alkoxy, dialkylamino, amino substituted by an alkyl group and a group selected from acyl aminocarbonyl, alkoxycarbonyl, and sulfonyl, lower alkyl substituted pyrazolyl, (optionally substituted lower alkyl), lower alkyl, and halo substituted lower alkyl. At least one chemical entity according to claim 6, characterized in that R 1 is selected from hydrogen, bromine, chlorine, fluoro, methyl, ethyl, propyl, hexenyl, butenyl, propenyl, vinyl, ethynyl, methoxy, ethoxy, methylsulfanyl, dimethylamino, and methyl substituted by one to three fluoro groups. At least one chemical entity according to claim 7, characterized in that R1 is selected from hydrogen, bromine, chlorine, fluoro, methyl, ethyl, n-propyl, isopropyl, dimethylamino, isobuten-1-yl, (Z ) -propen-1-yl, (E) -propen-1-yl, propen-2-yl, vinyl, ethynyl, methoxy, ethoxy, methylsulfanyl, and trifluoromethyl. At least one chemical entity according to any one of claims 1 to 8, characterized in that R 4 is selected from hydrogen, halo, acyl, optionally substituted alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, sulfanyl, optionally substituted amino, and optionally substituted alkoxycarbonyl. At least one chemical entity according to claim 9, characterized in that R 4 is selected from hydrogen, halo, acyl, optionally substituted lower alkyl, lower alkenyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, sulfanyl, optionally substituted amino, and optionally substituted lower alkoxycarbonyl. At least one chemical entity according to claim 10, characterized in that R 4 is selected from hydrogen, halo, acyl, lower alkyl, lower alkenyl, cycloalkyl, optionally substituted aminocarbonyl, sulfanyl, and lower alkoxycarbonyl. At least one chemical entity according to claim 11, characterized in that R 4 is selected from hydrogen, bromine, chlorine, fluoro, acetyl, methyl, ethyl, vinyl, cyclohexen-1-yl, methylcarbamoyl, dimethylcarbamoyl, methylsulfanyl, and methoxycarbonyl. At least one chemical entity according to any one of claims 1 to 4, characterized in that R4 and R1, taken together with any intervening atoms, form a fused ring system selected from optionally substituted fused aryl, optionally substituted fused cycloalkyl. and optionally substituted fused heterocycloolyl. At least one chemical entity according to claim 13, characterized in that R4 and R1 are taken together to form an optionally substituted benzo group. At least one chemical entity according to claim 14, characterized in that R4 and R1 are taken together to form a benzo group. At least one chemical entity according to claim 1, characterized in that the compound of formula I is chosen from [1 - ((IR) -1-methyl-2-morpholin-4-ylethyl) -6-bromoimidazo. [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6-ethynylimidazo [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6-methoxyimidazo [4,5-b] pyrazin-2-ol; [1- (1,1-dimethyl-2-morpholin-4-ylethyl) -6-bromoimidazo [4,5-b] pyrazin-2-ol; [6- (1α-1,2,3-triazol-4-yl) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6- (trifluoromethyl) imidazo [4,5-b] pyrazin-2-ol; [1 - [(1R) -1- (morpholin-4-ylmethyl) propyl] -6-ethynylimidazo [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6- {2- [1- (ethylpropyl) -2-hydroxyimidazo [4,5- e] pyrazin-6-yl] ethynyl} imidazo-4,5-b] pyrazin-2-ol; [6- (dimethylamino) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol; [6-ethyl-1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol; (E) -1- (pentan-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- [2-ol; (E) -1- (pentan-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- [2-ol; (E) -1-cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (E) -1-Cyclopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (E) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (E) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1- (1-phenylatyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (R) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) - (2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-6-yl) (4-methylpiperazin-1-yl) methanone; (S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (morpholino) methanone; (S) - (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) (pipendin-1-yl) methanone; (S) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1- (1-phenylethyl) -1H-imidazo [4,5-b] quinoxalin-2-ol; (S) -1- (1-phenylethyl) -6- (piperidin-1-ylmethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1- (1-phenylethyl) -6-propyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1- (1-phenylethyl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) -1- (2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-6-yl) ethanone; (S) -2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carbonitrile; (S) -2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-bpyrazine-6-carboxamide; (S) -2-Hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine [6-carboxylic acid; (S) -2-hydroxy-N, N-dimethyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine-6-carboxamide; (S) -2-hydroxy-N-methyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide; (S) -6 - ((4-methylpiperazin-1-yl) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6 - ((dimethylamino) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6- (2-hydroxypropan-2-yl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6- (2-methylprop-1-enyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6- (methylsulfonyl) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin- [2-ol; (S) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6- (morpholinomethyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Bromo-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-bromo-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-cyclohexenyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Cyclohexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-ethoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-ethyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (S) -6-hexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Isobutyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -6-Methoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; (S) -methyl 2-hydroxy-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazine [6-carboxylate; (S) -N.N-diethyl-2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide; (S) -N-benzyl-2-hydroxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazine-6-carboxamide; (S, E) -1- (1-phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin- [2-ol; (S, Z) -1- (1-phenylethyl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- [2-ol; (S, Z) -6- (hex-2-enyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin- [2-ol; (Z) -1- (pentan-3-yl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin- [2-ol; (Z) -1-cycloexyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (Z) -1-cyclopropyl-6- (prop-1-enyl) -1H-imidazot4,5-b] pyrazin-2-ol; (Z) -1-Isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin-2-ol; (Z) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [1- (1-aminobutan-2-yl) -6-bromo-1H-imidazo [4,5-b] pyrazin-2-ol; [1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [1- (2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-5-yl) ethanone; [1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-2,6-diol; [1- (pentan-3-yl) -1H-imidazo [4,5-b] quinoxalin-2-ol; [1- (pentan-3-yl) -5-vinyl-1H-imidazo [4,5-b] pyrazin-2-ol; [1- (pentan-3-yl) -6- (prop-1-ynyl) -1H-imidazo [4,5-b] pyrazin-2-ol; [1- (pentan-3-yl) -6- (trifluoromethyl) -1H-imidazo [4,5-b] pyrazin-2- [1-benzyl-6- (methylthio) -1H-imidazo [4,5 -b] pyrazin-2-ol; [1-benzyl-6-bromo-1H-imidazo [4,5-b] pyrazin-2-ol; [1-cyclohexyl-6- (methylthio) -1H-imidazo [4,5-bipyrazin-2-ol; [1-cyclopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol; [1-Isopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2-ol; [2- (6-bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) -1-morpholinobutan-1-one; 2- (6-Bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) butanoic acid; [2- (6-Bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) propane-1,3-diol; 2-hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxylic acid; [2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazine-6-carbonitrile; [2-hydroxy-N, N-dimethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazine-5-carboxamide; [2-hydroxy-N-methyl-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazine [5-carboxamide; [5- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [5-bromo-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2-ol; [5-ethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6- (methylsulfinyl) -1 - ((S) -1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin- [2-ol; [6- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6- (methylthio) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (1- (4- (methylsulfonyl) piperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (1- (4-methylpiperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (1- (dimethylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (1- (methylamino) butan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (1-methoxybutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (2-methyl-1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (2-morpholinoethyl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin- [2-ol; [6-bromo-1-cycloexyl-1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1-cyclopropyl-1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1-isopropyl-1H-imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1-tert-butyl-1H-imidazo [4,5-b] pyrazin-2-ol; [6-cyclopropyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-methoxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2-ol; [6-methyl-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2-ol; methyl 2-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazine-5-carboxylate; methyl 4- (2- (6-bromo-2-hydroxy-1H-imidazo [4,5-b] pyrazin-1-yl) butyl) piperazine-1-carboxylate; [1- (ethylpropyl) -6- (1-methylpyrazol-4-yl) imidazo [4,5-b] pyrazin-2-ol; [6-bromo-1- (propylbutyl) imidazo [4,5-b] pyrazin-2-ol; [1 - [(R 6) -3-methyl-1- (morpholin-4-ylmethyl) butyl] -6-bromoimidazo [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6-vinylimidazo [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6- (1-methylvinyl) imidazo [4,5-b] pyrazin-2-ol; [1- (ethylpropyl) -6- (methylethyl) imidazo [4,5-b] pyrazin-2-ol; [6-chloro-1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol; and [6- (dimethylamino) -1- (ethylpropyl) imidazo [4,5-b] pyrazin-2-ol. At least one chemical entity according to claim 1, characterized in that the compound of Formula II is chosen from (R) -6-bromo-1- (1-morpholinopropan-2-yl) -1 H -imidazo. [4,5-b] pyrazin-2 (3H) -one; [6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-Methoxy-1- (pentan-3-yl> -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one; [6-bromo-1- (2-methyl-1-yl) morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1- (pentan-3-yl) -6- (1H-1,2,3-triazol-2-one 4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1- (pentan-3-yl) -6- (trifluoromethyl) -1H-imidazo [4,5- b] pyrazin- [2 (3H) -one; (R) -6-ethynyl-1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) - [6 - ((2-hydroxy-1- (pentan-3-yl) -1H-imidazo [4,5-b 3 pyrazin-6-yl) ethynyl) -1- (pentan-3-yl) -1 H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6- (dimethylamino) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin- [2 (3H) -one; [6-ethyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (E) -1- (pentan-3-yl) 3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- [2 (3H) -one; (E) -1-cycloexyl-6- (prop-1 -enyl) -1H-imidazo [4,5-b] pyrazin- [2 (3H) -one; (E) -1-cyclopropyl-6- (prop-1-enyl) -1H-imidazo [4, 5-b] pyrazin- [2 (3H) -one; (E) -1-isopropyl-6- (prop-1-enyl) -1H-imidazo {4,5-b] pyrazin- [2 (3H) -one; (E) -6- (prop-1-enyl) -1- (tet rahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6-bromo-1- (1-hydroxybutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6-bromo-1- (1-morpholinobutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one; (R) -6-bromo-1- (1-morpholinopropan-2-yl) -1 H -imidazo [4,5-b 3 pyrazin-2 (3H) -one; (R) -6-bromo-1- (1-phenylatyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -1 H -imidazo [4,5-b] quinoxalin-2 (3H) -one; (S) -1- (1-phenylethyl) -6- (piperidin-1-ylmethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -6- (piperidine-1-carbonyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -6-propyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carbonitrile; (S) -2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; (S) -2-Oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5 b] pyrazine-5-carboxylic acid; (S) -6 - ((4-methylpiperazin-1-yl) methyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6 - ((dimethylamino) methyl) -2- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6- (2-hydroxypropan-2-yl) -1- (1-phenylethyl) -1H-imidazo [4,5 b] pyrazin-2 (3 H) -one; (S) -6- (2-methylprop-1-enyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6- (4-methylpiperazine-1-carbonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6- (methylsulfonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin- (3H) -one; (S) -6- (methylthio) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin- [2 (3H) -one; (S) -6- (morpholino-4-carbonyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6- (morpholinomethyl) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-Acetyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-bromo-1- (1-hydroxybutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3 H) -one; (S) -6-bromo-1- (1-morpholinobutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-bromo-1- (1-morpholinopropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-bromo-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-bromo-1-sec-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-cyclohexenyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin- (3H) -one; (S) -6-cyclohexyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-ethoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-ethyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-hexyl-1- (1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-Isobutyl-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -6-Methoxy-1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -methyl 2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxylate; (S) -N, N-diethyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; (S) -N, N-dimethyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; (S) -N-benzyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; (S) -N-methyl-2-oxo-3- (1-phenylethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; [2 (3H) -one; [2 (3H) -one; [2 (3H) -one; [2 (3H) -one; [2 (3H) -one; [2 (3H) -one; (S, E) -1- (1-phenylethyl) -6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin- (S, Z) -1- (1-phenylethyl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- (S, Z) -6- (hex-2-enyl) -1- (1-phenylethyl) -1H- imidazo [4,5-b3pyrazin- (Z) -1- (pentan-3-yl) -6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- (Z) -1 -cyclohexyl-6- (prop-1-enyl) -1H-imidazo [4,5-b] pyrazin- (Z) -1-cyclopropyl-6- (prop-1-enyl) -1H-imidazo [4 , 5-b] pyrazin- (Z) -1-isopropyl-6- (prop-1-enyl) -1 H -imidazo [4,5-b] pyrazin- [2 (3H) -one; (Z) -6- (prop-1-enyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1- (1-aminobutan-2-yl) -6-bromo-1H-imidazo [4,5-b] pyrazin- [2 (3H) -one; one; [2 (3H) -one; [2 (3H) -one; [1- (1-morpholinobutan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) - [1- (pentan-3-yl) -1H-imidazo [4,5- b] pyrazin-2 (3H) -one; [1- (pentan-3-yl) -1H-imidazo [4,5-b] quinoxalin-2 (3H) -one; [1- (pentan-3-yl) -5-vinyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1- (pentan-3-yl) -6- (prop-1-yl) -1H-imidazo [4,5-b] pyrazin- [1- (pentan-3-yl) -6- (trifluoromethyl) -1H-imidazo [4,5-b] pyrazin- [1-benzyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1-benzyl-6-bromo-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1-cyclohexyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1-cyclopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1-Isopropyl-6- (methylthio) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 2- (6-Bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyrazin- [1-yl) butanoic acid; 2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxylic acid; [2-oxo-3- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carbonitrile; [5- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [5-acetyl-1-pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [5-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [5-ethyl-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; [6- (methylsulfinyl) -1 - ((S) -1-phenylethyl) -1 H -imidazo [4,5-b] pyrazin- [2 (3H) -one; [6- (methylthio) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6- (methylthio) -1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b 3 pyrazin-2 (3H) -one; [6-bromo-1- (1- (4- (methylsulfonyl) piperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (1- (4-methylpiperazin-1-yl) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (1- (dimethylamino) butan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (1- (methylamino) butan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (1,3-dihydroxypropan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (1-methoxybutan-2-yl) -1 H -imidazo [4,5-b] pyrazin- [2 (3H) -one; [6-bromo-1- (1-morpholine-1-oxobutan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (2-methyl-1-morpholinopropan-2-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (2-morpholininoethyl) -1H-imidazo [4,5-b] pyrazin-2- (3H) -one; [6-bromo-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1-cyclohexyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1-cyclopropyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1-isopropyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1-tert-butyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-cyclopropyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-ethynyl-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-hydroxy-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; [6-methoxy-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-methyl-1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; methyl 2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxylate; methyl 4- (2- (6-bromo-2-oxo-2,3-dihydro-1 H -imidazo [4,5-b] pyrazin-1-yl) butyl) piperazine-1-carboxylate; N.N-dimethyl-2-οχο-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; N-methyl-2-oxo-1- (pentan-3-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrazine-5-carboxamide; [6- (1-methyl-1H-pyrazol-4-yl) -1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [6-bromo-1- (heptan-4-yl) -1 H -imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6-bromo-1- (4-methyl-1-morpholinopentan-2-yl) -1H-imidazo [4,5-b] pyrazin-2 (3 H) -one; [1- (pentan-3-yl) -6-vinyl-1H-imidazo [4,5-b] pyrazin-2 (3H) -one; [1- (pentan-3-yl) -6- (prop-1-en-2-yl) -1H-imidazo [4,5-b] pyrazin- [6-isopropyl-1- (pentan-3-yl) ) -1 H -imidazo [4,5-b] pyrazin-2 (3H) - [6-chloro-1- (pentan-3-yl) -1H-imidazo [4,5-b] pyrazin-2 (3H ) -one; and [6- (dimethylamino) -1- (pentan-3-yl) -1 H -imidazo [4,5-b] pyrazin-2-one Pharmaceutically acceptable composition, characterized in that it comprises a pharmaceutically acceptable carrier and at least one chemical entity as defined in any one of claims 1 to 17. Pharmaceutically acceptable composition according to Claim 18, characterized in that it is formulated in a chosen form of tablets, capsules, powders, liquids, suspensions, suppositories and aerosols. A pharmaceutical composition comprising a pharmaceutical composition as defined in claim 18 or 19 and instructions for using the composition to treat a patient suffering from a chosen disease of obesity, sarcopenia, wasting syndrome, frailty, cachexia, spasm. muscle, weakness <formula> formula see original document page 103 </formula> post-surgery and post-traumatic and a neuromuscular disease. A pharmaceutical composition comprising a pharmaceutical composition as defined in claim 18 or 19 and instructions for using the composition to treat a patient suffering from a disease responsive to modulation of one or more skeletal myosin, skeletal actin, tropomyosin. skeletal, skeletal troponin C, skeletal troponin I, skeletal troponin T, skeletal muscle and skeletal sarcomere. 22. A method for treating a patient who has a disease chosen from obesity, sarcopenia, wasting syndrome, frailty, cachexia, muscle spasm, post-surgical and post-traumatic muscle weakness, and a neuromuscular disease, a method characterized by understanding administering to the therapeutically effective amount of at least one chemical entity as defined in any one of claims 1 to 17. 23. A method for treating a patient having a disease responsive to the modulation of one or more skeletal myosin, skeletal actin, skeletal thromomyosin, skeletal troponin C, skeletal troponin 1, skeletal troponin T, skeletal muscle and skeletal sarcomere, said method characterized by It is understood to administer to the patient an effective amount of at least one chemical entity as defined in any one of claims 1 to 17.